Exendin agonist compounds

ABSTRACT

Novel exendin agonist compounds are provided. These compounds are useful in treating diabetes and conditions which would be benefited by lowering plasma glucose or delaying and/or slowing gastric emptying.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.09/554,533 filed Jul. 11, 2002, issued as U.S. Pat. No. 7,223,725, whichis a §371 of PCT/US98/24210 filed Nov. 13, 1998, which claims priorityto U.S. Provisional Application No. 60/065,442, filed Nov. 14, 1997, thecontents of which are hereby incorporated by reference in theirentirety.

FIELD OF THE INVENTION

The present invention relates to novel compounds which have activity asexendin agonists. These compounds are useful in treatment of Type I andII diabetes, in treatment of disorders which would be benefited byagents which lower plasma glucose levels and in treatment of disorderswhich would be benefited with agents useful in delaying and/or slowinggastric emptying.

BACKGROUND

The following description includes information that may be useful inunderstanding the present invention. It is not an admission that any ofthe information provided herein is prior art to the presently claimedinvention, nor that any of the publications specifically or implicitlyreferenced are prior art to that invention.

Exendin

The exendins are peptides that are found in venom of the Gila-monster, alizard endogenous to Arizona and Northern Mexico. Exendin-3 (SEQ IDNO:1) is present in the venom of Heloderma horridum, and exendin-4 (SEQID NO:2) is present in the venom of Heloderma suspectum (Eng, J., etal., J. Biol. Chem., 265:20259-62, 1990; Eng., J., et al., J. Biol.Chem., 267:7402-05, 1992). The amino acid sequence of exendin-3 is shownin FIG. 1. The amino acid sequence of exendin-4 is shown in FIG. 2. Theexendins have some sequence similarity to several members of theglucagon-like peptide family, with the highest homology, 53%, being toGLP-1[7-36]NH₂ (SEQ ID NO:3) (Goke, et al., J. Biol. Chem.,268:19650-55, 1993). GLP-1[7-36]NH₂, also known as proglucagon[78-107]or simply “GLP-1” as used most often herein, has an insulinotropiceffect, stimulating insulin secretion from pancreatic β-cells. GLP-1also inhibits glucagon secretion from pancreatic α-cells (Ørsov, et al.,Diabetes, 42:658-61, 1993; D'Alessio, et al., J. Clin. Invest.,97:133-38, 1996). The amino acid sequence of GLP-1 is shown in FIG. 3.GLP-1 is reported to inhibit gastric emptying (Willms B, et al., J ClinEndocrinol Metab 81 (1): 327-32, 1996; Wettergren A, et al., Dig Dis Sci38 (4): 665-73, 1993), and gastric acid secretion. Schjoldager B T, etal., Dig Dis Sci 34 (5): 703-8, 1989; O'Halloran D J, et al., JEndocrinol 126 (1): 169-73, 1990; Wettergren A, et al., Dig Dis Sci 38(4): 665-73, 1993). GLP-1[7-37], which has an additional glycine residueat its carboxy terminus, also stimulates insulin secretion in humans(Ørsov, et al., Diabetes, 42:658-61, 1993).

A transmembrane G-protein adenylate-cyclase-coupled receptor believed tobe responsible for the insulinotropic effect of GLP-1 has been clonedfrom a β-cell line (Thorens, Proc. Natl. Acad. Sci. USA 89:8641-45,1992), herein after referred to as the “cloned GLP-1 receptor.”Exendin-4 is reportedly acts at GLP-1 receptors on insulin-secretingβTC1 cells, at dispersed acinar cells from guinea pig pancreas, and atparietal cells from stomach; the peptide is also reported to stimulatesomatostatin release and inhibit gastrin release in isolated stomachs(Goke, et al., J. Biol. Chem. 268:19650-55, 1993; Schepp, et al., Eur.J. Pharmacol., 69:183-91, 1994; Eissele, et al., Life Sci., 55:629-34,1994). Exendin-3 and exendin-4 were reportedly found to stimulate cAMPproduction in, and amylase release from, pancreatic acinar cells(Malhotra, R., et al., Regulatory Peptides, 41:149-56, 1992; Raufman, etal., J. Biol. Chem. 267:21432-37, 1992; Singh, et al., Regul. Pept.53:47-59, 1994). Based on their insulinotropic activities, the use ofexendin-3 and exendin-4 for the treatment of diabetes mellitus and theprevention of hyperglycemia has been proposed (Eng, U.S. Pat. No.5,424,286).

Agents which serve to delay gastric emptying have found a place inmedicine as diagnostic aids in gastro-intestinal radiologicexaminations. For example, glucagon is a polypeptide hormone which isproduced by the α cells of the pancreatic islets of Langerhans. It is ahyperglycemic agent which mobilizes glucose by activating hepaticglycogenolysis. It can to a lesser extent stimulate the secretion ofpancreatic insulin. Glucagon is used in the treatment of insulin-inducedhypoglycemia, for example, when administration of glucose intravenouslyis not possible. However, as glucagon reduces the motility of thegastro-intestinal tract it is also used as a diagnostic aid ingastro-intestinal radiological examinations. Glucagon has also been usedin several studies to treat various painful gastro-intestinal disordersassociated with spasm. Daniel, et al. (Br. Med. J., 3:720, 1974)reported quicker symptomatic relief of acute diverticulitis in patientstreated with glucagon compared with those who had been treated withanalgesics or antispasmodics. A review by Glauser, et al. (J. Am. Coll.Emergency Physns, 8:228, 1979) described relief of acute esophageal foodobstruction following glucagon therapy. In another study glucagonsignificantly relieved pain and tenderness in 21 patients with biliarytract disease compared with 22 patients treated with placebo (M. J.Stower, et al., Br. J. Surg., 69:591-2, 1982).

Methods for regulating gastrointestinal motility using amylin agonistsare described in International Application No. PCT/US94/10225, publishedMar. 16, 1995.

Methods for regulating gastrointestinal motility using exendin agonistsare described in U.S. patent application Ser. No. 08/908,867, filed Aug.8, 1997 entitled “Methods for Regulating Gastrointestinal Motility,”which application is a continuation-in-part of U.S. patent applicationSer. No. 08/694,954 filed Aug. 8, 1996.

Methods for reducing food intake using exendin agonists are described inU.S. patent application Ser. No. 09/003,869, filed Jan. 7, 1998,entitled “Use of Exendin and Agonists Thereof for the Reduction of FoodIntake,” which claims the benefit of U.S. Provisional Application Nos.60/034,905, filed Jan. 7, 1997, 60/055,404, filed Aug. 7, 1997,60/065,442, filed Nov. 14, 1997 and 60/066,029, filed Nov. 14, 1997.

Novel exendin agonist compounds are described in PCT Application SerialNo. PCT/US98/16387 filed Aug. 6, 1998, entitled “Novel Exendin AgonistCompounds,” claiming the benefit of U.S. Provisional Application Ser.No. 60/055,404, filed Aug. 8, 1997. Other novel exendin agonistcompounds are described in PCT Application Serial No. PCT/US98/24210filed Nov. 13, 1998, entitled “Novel Exendin Agonist Compounds,” whichclaims the benefit of U.S. Provisional Application No. 60/066,029 filedNov. 14, 1997.

SUMMARY OF THE INVENTION

According to one aspect, the present invention provides novel exendinagonist compounds which exhibit advantageous properties which includeeffects in slowing gastric emptying and lowering plasma glucose levels.

According to the present invention, provided are compounds of theformula (I) (SEQ ID NO:4):

Xaa₁ Xaa₂ Xaa₃ Gly Xaa₅ Xaa₆ Xaa₇ Xaa₈ Xaa₉ Xaa₁₀ Xaa₁₁ Xaa₁₂ Xaa₁₃Xaa₁₄ Xaa₁₅ Xaa₁₆ Xaa₁₇ Ala Xaa₁₉ Xaa₂₀ Xaa₂₁ Xaa₂₂ Xaa₂₃ Xaa₂₄ Xaa₂₅Xaa₂₆ Xaa₂₇ Xaa₂₈-Z₁; wherein Xaa₁ is His, Arg or Tyr; Xaa₂ is Ser, Gly,Ala or Thr; Xaa₃ is Asp or Glu; Xaa₅ is Ala or Thr; Xaa₆ is Ala, Phe,Tyr or naphthylalanine; Xaa₇ is Thr or Ser; Xaa₈ is Ala, Ser or Thr;Xaa₉ is Asp or Glu; Xaa₁₀ is Ala, Leu, Ile, Val, pentylglycine or Met;Xaa₁₁ is Ala or Ser; Xaa₁₂ is Ala or Lys; Xaa₁₃ is Ala or Gln; Xaa₁₄ isAla, Leu, Ile, pentylglycine, Val or Met; Xaa₁₅ is Ala or Glu; Xaa₁₆ isAla or Glu; Xaa₁₇ is Ala or Glu; Xaa₁₉ is Ala or Val; Xaa₂₀ is Ala orArg; Xaa₂₁ is Ala or Leu; Xaa₂₂ is Phe, Tyr or naphthylalanine; Xaa₂₃ isIle, Val, Leu, pentylglycine, tert-butyl- glycine or Met; Xaa₂₄ is Ala,Glu or Asp; Xaa₂₅ is Ala, Trp, Phe, Tyr or naphthylalanine; Xaa₂₆ is Alaor Leu; Xaa₂₇ is Ala or Lys; Xaa₂₈ is Ala or Asn; Z₁ is —OH,       —NH₂

Gly-Z₂, Gly Gly-Z₂, Gly Gly Xaa₃₁-Z₂, Gly Gly Xaa₃₁ Ser-Z₂, Gly GlyXaa₃₁ Ser Ser-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly-Z₂, Gly Gly Xaa₃₁ Ser SerGly Ala-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆-Z₂, Gly Gly Xaa₃₁ SerSer Gly Ala Xaa₃₆ Xaa₃₇-Z₂ or Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇Xaa₃₈- Z₂; Xaa₃₁, Xaa₃₆, Xaa₃₇ and Xaa₃₈ are independently Pro,homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine,N-alkylpentylglycine or N-alkylalanine; and Z₂ is —OH or —NH₂;provided that no more than three of Xaa₃, Xaa₅, Xaa₆, Xaa₈, Xaa₁₀,Xaa₁₁, Xaa₁₂, Xaa₁₃, Xaa₁₄, Xaa₁₅, Xaa₁₆, Xaa₁₇, Xaa₁₉, Xaa₂₀, Xaa₂₁,Xaa₂₄, Xaa₂₅, Xaa₂₆, Xaa₂₇ and Xaa₂₈ are Ala. Also included within thescope of the present invention are pharmaceutically acceptable salts ofthe compounds of formula (I) and pharmaceutical compositions includingsaid compounds and salts thereof.

Also within the scope of the present invention are narrower genera ofcompounds having peptides of various lengths, for example genera ofcompounds which do not include peptides having a length of 28, 29 or 30amino acid residues, respectively. Additionally, the present inventionincludes narrower genera of compounds having particular amino acidsequences, for example, compounds of the formula (I) (SEQ ID NO:4):

Xaa₁ Xaa₂ Xaa₃ Gly Xaa₅ Xaa₆ Xaa₇ Xaa₈ Xaa₉ Xaa₁₀ Xaa₁₁ Xaa₁₂ Xaa₁₃Xaa₁₄ Xaa₁₅ Xaa₁₆ Xaa₁₇ Ala Xaa₁₈ Xaa₁₉ Xaa₂₀ Xaa₂₁ Xaa₂₂ Xaa₂₃ Xaa₂₄Xaa₂₅ Xaa₂₆ Xaa₂₇ Xaa₂₈-Z₁; wherein Xaa₁ is His or Arg; Xaa₂ is Gly orAla; Xaa₃ is Asp or Glu; Xaa₅ is Ala or Thr; Xaa₆ is Ala, Phe ornaphthylalanine; Xaa₇ is Thr or Ser; Xaa₈ is Ala, Ser or Thr; Xaa₉ isAsp or Glu; Xaa₁₀ is Ala, Leu or pentylglycine; Xaa₁₁ is Ala or Ser;Xaa₁₂ is Ala or Lys; Xaa₁₃ is Ala or Gln; Xaa₁₄ is Ala, Leu orpentylglycine; Xaa₁₅ is Ala or Glu; Xaa₁₆ is Ala or Glu; Xaa₁₇ is Ala orGlu; Xaa₁₉ is Ala or Val; Xaa₂₀ is Ala or Arg; Xaa₂₁ is Ala or Leu;Xaa₂₂ is Phe or naphthylalanine; Xaa₂₃ is Ile, Val or tert-butylglycine;Xaa₂₄ is Ala, Glu or Asp; Xaa₂₅ is Ala, Trp, or Phe; Xaa₂₆ is Ala orLeu; Xaa₂₇ is Ala or Lys; Xaa₂₈ is Ala or Asn; Z₁ is —OH,       —NH₂,

Gly-Z₂, Gly Gly -Z₂, Gly Gly Xaa₃₁-Z₂, Gly Gly Xaa₃₁ Ser-Z₂, Gly GlyXaa₃₁ Ser Ser-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly-Z₂, Gly Gly Xaa₃₁ Ser SerGly Ala-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆-Z₂, Gly Gly Xaa₃₁ SerSer Gly Ala Xaa₃₆ Xaa₃₇-Z₂ or Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇Xaa₃₈- Z₂; Xaa₃₁, Xaa₃₆, Xaa₃₇ and Xaa₃₈ are independently selected fromthe group consisting of Pro, homo- proline, thioproline andN-methylylalanine; and Z₂ is —OH or —NH₂;provided that no more than three of Xaa₃, Xaa₅, Xaa₆, Xaa₈, Xaa₁₀,Xaa₁₁, Xaa₁₂, Xaa₁₃, Xaa₁₄, Xaa₁₅, Xaa₁₆, Xaa₁₇, Xaa₁₉, Xaa₂₀, Xaa₂₁,Xaa₂₄, Xaa₂₅, Xaa₂₆, Xaa₂₇ and Xaa₂₈ are Ala; and pharmaceuticallyacceptable salts thereof.

Also provided are compounds of the formula (II) (SEQ ID NO:66):

                  5                     10 Xaa₁ Xaa₂ Xaa₃ Gly Xaa₅ Xaa₆Xaa₇ Xaa₈ Xaa₉ Xaa₁₀ Xaa₁₁ Xaa₁₂ Xaa₁₃ Xaa₁₄ Xaa₁₅ Xaa₁₆ Xaa₁₇ Ala Xaa₁₉Xaa₂₀ Xaa₂₁ Xaa₂₂ Xaa₂₃ Xaa₂₄ Xaa₂₅ Xaa₂₆ X₁ -Z₁; wherein Xaa₁ is His,Arg, Tyr or 4-imidazopropionyl; Xaa₂ is Ser, Gly, Ala or Thr; Xaa₃ isAsp or Glu; Xaa₅ is Ala or Thr; Xaa₆ is Ala, Phe, Tyr ornaphthylalanine; Xaa₇ is Thr or Ser; Xaa₈ is Ala, Ser or Thr; Xaa₉ isAsp or Glu; Xaa₁₀ is Ala, Leu, Ile, Val, pentylglycine or Met; Xaa₁₁ isAla or Ser; Xaa₁₂ is Ala or Lys; Xaa₁₃ is Ala or Gln; Xaa₁₄ is Ala, Leu,Ile, pentylglycine, Val or Met; Xaa₁₅ is Ala or Glu; Xaa₁₆ is Ala orGlu; Xaa₁₇ is Ala or Glu; Xaa₁₉ is Ala or Val; Xaa₂₀ is Ala or Arg;Xaa₂₁ is Ala, Leu or Lys-NH^(ε)-R where R is Lys, Arg, C₁-C₁₀ straightchain or branched alkanoyl or cycloalkylalkanoyl; Xaa₂₂ is Phe, Tyr ornaphthylalanine; Xaa₂₃ is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met; Xaa₂₄ is Ala, Glu or Asp; Xaa₂₅ is Ala, Trp, Phe,Tyr or naphthylalanine; Xaa₂₆ is Ala or Leu; X₁ is Lys Asn, Asn Lys,Lys-NH^(ε)-R Asn, Asn Lys- NH^(ε)-R, Lys-NH^(ε)-R Ala, Ala Lys-NH^(ε)-Rwhere R is Lys, Arg, C₁-C₁₀ straight chain or branched alkanoyl orcycloalkylalkanoyl Z₁ is —OH,

—NH₂, Gly-Z₂, Gly Gly-Z₂, Gly Gly Xaa₃₁-Z₂, Gly Gly Xaa₃₁ Ser-Z₂, GlyGly Xaa₃₁ Ser Ser-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly-Z₂, Gly Gly Xaa₃₁ SerSer Gly Ala-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆-Z₂, Gly Gly Xaa₃₁Ser Ser Gly Ala Xaa₃₆ Xaa₃₇-Z₂ or Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆Xaa₃₇ Xaa₃₈- Z₂; wherein Xaa₃₁, Xaa₃₆, Xaa₃₇ and Xaa₃₈ are independentlyselected from the group consisting of Pro, homoproline, 3Hyp, 4Hyp,thioproline, N-alkylglycine, N-alkylpentylglycine and N-alkylalanine;and Z₂ is —OH or —NH₂;provided that no more than three of Xaa₃, Xaa₅, Xaa₆, Xaa₈, Xaa₁₀,Xaa₁₁, Xaa₁₂, Xaa₁₃, Xaa₁₄, Xaa₁₅, Xaa₁₆, Xaa₁₇, Xaa₁₉, Xaa₂₀, Xaa₂₁,Xaa₂₄, Xaa₂₅, and Xaa₂₆ are Ala. Also within the scope of the presentinvention are pharmaceutically acceptable salts of the compounds offormula (II) and pharmaceutical compositions including said compoundsand salts thereof.

Preferred exendin agonist compounds of formula (II) include thosewherein Xaa₁ is H is, Tyr or 4-imidazopropionyl. More preferably Xaa₁ isHis. Also, preferred are those compounds of formula (II) wherein Xaa₁ is4-imidazopropionyl.

Preferred are those compounds of formula (II) wherein Xaa₂ is Gly.

Preferred compounds of formula (II) are those wherein Xaa₁₄ is Leu,pentylglycine or Met.

Preferred compounds of formula (II) are those wherein Xaa₂₅ is Trp orPhe.

According to one aspect, preferred are compounds of formula (II) whereinXaa₆ is Phe or naphthylalanine; Xaa₂₂ is Phe or naphthylalanine; andXaa₂₃ is Ile or Val. More preferably, Z₁ is —NH₂. According to oneaspect, especially preferred are such compounds of formula (II) whereinXaa₃₁, Xaa₃₆, Xaa₃₇ and Xaa₃₈ are independently selected from the groupconsisting of Pro, homoproline, thioproline and N-alkylalanine. Morepreferably, Z₂ is —NH₂.

Preferred compounds of formula (II) include those wherein X₁ is Lys Asn,Lys-NH^(ε)—R Asn, or Lys-NH^(ε)—R Ala where R is Lys, Arg, C₁-C₁₀straight chain or branched alkanoyl. Especially preferred compounds offormula (II) include Compound Nos. 62-69 (SEQ ID NOs:67-74).

DEFINITIONS

In accordance with the present invention and as used herein, thefollowing terms are defined to have the following meanings, unlessexplicitly stated otherwise.

The term “amino acid” refers to natural amino acids, unnatural aminoacids, and amino acid analogs, all in their D and L stereoisomers iftheir structure allow such stereoisomeric forms. Natural amino acidsinclude alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid(Asp), cysteine (Cys), glutamine (Gln), glutamic acid (Glu), glycine(Gly), histidine (H is), isoleucine (Ile), leucine (Leu), Lysine (Lys),methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser),threonine (Thr), typtophan (Trp), tyrosine (Tyr) and valine (Val).Unnatural amino acids include, but are not limited toazetidinecarboxylic acid, 2-aminoadipic acid, 3-aminoadipic acid,beta-alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyricacid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyricacid, 3-aminoisbutyric acid, 2-aminopimelic acid, tertiary-butylglycine,2,4-diaminoisobutyric acid, desmosine, 2,2′-diaminopimelic acid,2,3-diaminopropionic acid, N-ethylglycine, N-ethylasparagine,homoproline, hydroxylysine, allo-hydroxylysine, 3-hydroxyproline,4-hydroxyproline, isodesmosine, allo-isoleucine, N-methylalanine,N-methylglycine, N-methylisoleucine, N-methylpentylglycine,N-methylvaline, naphthalanine, norvaline, norleucine, ornithine,pentylglycine, pipecolic acid and thioproline. Amino acid analogsinclude the natural and unnatural amino acids which are chemicallyblocked, reversibly or irreversibly, or modified on their N-terminalamino group or their side-chain groups, as for example, methioninesulfoxide, methionine sulfone, S-(carboxymethyl)-cysteine,S-(carboxymethyl)-cysteine sulfoxide and S-(carboxymethyl)-cysteinesulfone.

The term “amino acid analog” refers to an amino acid wherein either theC-terminal carboxy group, the N-terminal amino group or side-chainfunctional group has been chemically codified to another functionalgroup. For example, aspartic acid-(beta-methyl ester) is an amino acidanalog of aspartic acid; N-ethylglycine is an amino acid analog ofglycine; or alanine carboxamide is an amino acid analog of alanine.

The term “amino acid residue” refers to radicals having the structure:(1) —C(O)—R—NH—, wherein R typically is —CH(R′)—, wherein R′ is an aminoacid side chain, typically H or a carbon containing substitutent; or (2)

wherein p is 1, 2 or 3 representing the azetidinecarboxylic acid,proline or pipecolic acid residues, respectively.

The term “lower” referred to herein in connection with organic radicalssuch as alkyl groups defines such groups with up to and including about6, preferably up to and including 4 and advantageously one or two carbonatoms. Such groups may be straight chain or branched chain.

“Pharmaceutically acceptable salt” includes salts of the compounds ofthe present invention derived from the combination of such compounds andan organic or inorganic acid. In practice the use of the salt formamounts to use of the base form. The compounds of the present inventionare useful in both free base and salt form, with both forms beingconsidered as being within the scope of the present invention.

In addition, the following abbreviations stand for the following:

“ACN” or “CH₃CN” refers to acetonitrile.

“Boc”, “tBoc” or “Tboc” refers to t-butoxy carbonyl.

“DCC” refers to N,N′-dicyclohexylcarbodiimide.

“Fmoc” refers to fluorenylmethoxycarbonyl.

“HBTU” refers to 2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluroniumhexafluorophosphate.

“HOBt” refers to 1-hydroxybenzotriazole monohydrate.

“homoP” or hPro” refers to homoproline.

“MeAla” or “Nme” refers to N-methylalanine.

“naph” refers to naphthylalanine.

“pG” or pGly” refers to pentylglycine.

“tBuG” refers to tertiary-butylglycine.

“ThioP” or tPro” refers to thioproline.

“3Hyp” refers to 3-hydroxyproline

“4Hyp” refers to 4-hydroxyproline

“NAG” refers to N-alkylglycine

“NAPG” refers to N-alkylpentylglycine

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the amino acid sequence for exendin-3 (SEQ ID NO:1).

FIG. 2 depicts the amino acid sequence for exendin-4 (SEQ ID NO:2).

FIG. 3 depicts the amino acid sequence for GLP-1[7-36]NH₂ (GLP-1) (SEQID NO:3).

FIGS. 4A-B depict the amino acid sequences for certain compounds of thepresent invention, Compounds 1-61 (SEQ ID NOs:5-65).

FIG. 5 depicts the effect on lowering blood glucose of variousconcentrations of Compound 3 (SEQ ID NO:7).

FIG. 6 depicts the effect on gastric emptying of various concentrationsof Compound 2 (SEQ ID NO:6).

FIG. 7 depicts a comparison of effects on gastric emptying of variousconcentrations of Compound 3 (SEQ ID NO:7).

FIG. 8 depicts a comparison of effects on gastric emptying of variousconcentrations of Compound 10 (SEQ ID NO:14).

FIG. 9 depicts a comparison of effects on gastric emptying of variousconcentrations of Compound 13 (SEQ ID NO:17).

FIG. 10 depicts the amino acid sequences for certain compounds of thepresent invention, Compound Nos. 62-69 (SEQ ID NOs:67-74).

DETAILED DESCRIPTION OF THE INVENTION

According to the present invention, provided are compounds of theformula (I) (SEQ ID NO:4):

Xaa₁ Xaa₂ Xaa₃ Gly Xaa₅ Xaa₆ Xaa₇ Xaa₈ Xaa₉ Xaa₁₀ Xaa₁₁ Xaa₁₂ Xaa₁₃Xaa₁₄ Xaa₁₅ Xaa₁₆ Xaa₁₇ Ala Xaa₁₉ Xaa₂₀ Xaa₂₁ Xaa₂₂ Xaa₂₃ Xaa₂₄ Xaa₂₅Xaa₂₆ Xaa₂₇ Xaa₂₈-Z₁; wherein Xaa₁ is His, Arg or Tyr; Xaa₂ is Ser, Gly,Ala or Thr; Xaa₃ is Asp or Glu; Xaa₅ is Ala or Thr; Xaa₆ is Ala, Phe,Tyr or naphthylalanine; Xaa₇ is Thr or Ser; Xaa₈ is Ala, Ser or Thr;Xaa₉ is Asp or Glu; Xaa₁₀ is Ala, Leu, Ile, Val, pentylglycine or Met;Xaa₁₁ is Ala or Ser; Xaa₁₂ is Ala or Lys; Xaa₁₃ is Ala or Gln; Xaa₁₄ isAla, Leu, Ile, pentylglycine, Val or Met; Xaa₁₅ is Ala or Glu; Xaa₁₆ isAla or Glu; Xaa₁₇ is Ala or Glu; Xaa₁₉ is Ala or Val; Xaa₂₀ is Ala orArg; Xaa₂₁ is Ala or Leu; Xaa₂₂ is Phe, Tyr or naphthylalanine; Xaa₂₃ isIle, Val, Leu, pentylglycine, tert- butylglycine or Met; Xaa₂₄ is Ala,Glu or Asp; Xaa₂₅ is Ala, Trp, Phe, Tyr or naphthylalanine; Xaa₂₆ is Alaor Leu; Xaa₂₇ is Ala or Lys; Xaa₂₈ is Ala or Asn; Z₁ is —OH,       —NH₂

Gly-Z₂, Gly Gly-Z₂, Gly Gly Xaa₃₁-Z₂, Gly Gly Xaa₃₁ Ser-Z₂, Gly GlyXaa₃₁ Ser Ser-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly-Z₂, Gly Gly Xaa₃₁ Ser SerGly Ala-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆-Z₂, Gly Gly Xaa₃₁ SerSer Gly Ala Xaa₃₆ Xaa₃₇-Z₂ or Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇Xaa₃₈- Z₂; Xaa₃₁, Xaa₃₆, Xaa₃₇ and Xaa₃₈ are independently Pro,homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine,N-alkylpentylglycine or N-alkylalanine; and Z₂ is —OH or —NH₂;provided that no more than three of Xaa₃, Xaa₅, Xaa₆, Xaa₈, Xaa₁₀,Xaa₁₁, Xaa₁₂, Xaa₁₃, Xaa₁₄, Xaa₁₅, Xaa₁₆, Xaa₁₇, Xaa₁₉, Xaa₂₀, Xaa₂₁,Xaa₂₄, Xaa₂₅, Xaa₂₆, Xaa₂₇ and Xaa₂₈ are Ala. Also within the scope ofthe present invention are pharmaceutically acceptable salts of thecompounds for formula (I) and pharmaceutical compositions including saidcompounds and salts thereof.

Preferred N-alkyl groups for N-alkylglycine, N-alkylpentylglycine andN-alkylalanine include lower alkyl groups preferably of 1 to about 6carbon atoms, more preferably of 1 to 4 carbon atoms. Suitable compoundsof formula (I) include those identified in Examples 1-61 (“Compounds1-61,” respectively) (SEQ ID NOs:5-65), as well as those correspondingcompounds identified in Examples 70 and 71.

Preferred such exendin agonist compounds include those wherein Xaa₁ isHis or Tyr. More preferably Xaa₁ is His.

Preferred are those such compounds wherein Xaa₂ is Gly.

Preferred are those such compounds wherein Xaa₁₄ is Leu, pentylglycineor Met.

Preferred such compounds are those wherein Xaa₂₅ is Trp or Phe.

Preferred compounds of formula (I) are those where Xaa₆ is Phe ornaphthylalanine; Xaa₂₂ is Phe of naphthylalanine and Xaa₂₃ is Ile orVal.

Preferred are compounds of formula (I) wherein Xaa₃₁, Xaa₃₆, Xaa₃₇ andXaa₃₈ are independently selected from Pro, homoproline, thioproline andN-alkylalanine.

Preferably Z₁ is —NH₂.

Preferable Z₂ is —NH₂.

According to one aspect, preferred are compounds of formula (I) whereinXaa₁ is His or Tyr, more preferably His; Xaa₂ is Gly; Xaa₆ is Phe ornaphthylalanine; Xaa₁₄ is Leu, pentylglycine or Met; Xaa₂₂ is Phe ornaphthylalanine; Xaa₂₃ is Ile or Val; Xaa₃₁, Xaa₃₆, Xaa₃₇ and Xaa₃₈ areindependently selected from Pro, homoproline, thioproline orN-alkylalanine. More preferably Z₁ is —NH₂.

According to an especially preferred aspect, especially preferredcompounds include those of formula (I) wherein: Xaa₁ is His or Arg; Xaa₂is Gly or Ala; Xaa₃ is Asp or Glu; Xaa₅ is Ala or Thr; Xaa₆ is Ala, Pheor nephthylalaine; Xaa₇ is Thr or Ser; Xaa₈ is Ala, Ser or Thr; Xaa₉ isAsp or Glu; Xaa₁₀ is Ala, Leu or pentylglycine; Xaa₁₁ is Ala or Ser;Xaa₁₂ is Ala or Lys; Xaa₁₃ is Ala or Gln; Xaa₁₄ is Ala, Leu orpentylglycine; Xaa₁₅ is Ala or Glu; Xaa₁₆ is Ala or Glu; Xaa₁₇ is Ala orGlu; Xaa₁₉ is Ala or Val; Xaa₂₀ is Ala or Arg; Xaa₂₁ is Ala or Leu;Xaa₂₂ is Phe or naphthylalanine; Xaa₂₃ is Ile, Val or tert-butylglycine;Xaa₂₄ is Ala, Glu or Asp; Xaa₂₅ is Ala, Trp or Phe; Xaa₂₆ is Ala or Leu;Xaa₂₇ is Ala or Lys; Xaa₂₈ is Ala or Asn; Z₁ is —OH, —NH₂, Gly-Z₂, GlyGly-Z₂, Gly Gly Xaa₃₁-Z₂, Gly Gly Xaa₃, Ser-Z₂, Gly Gly Xaa₃₁ SerSer-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly Ala-Z₂,Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly AlaXaa₃₆ Xaa₃₇-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇ Xaa₃₈-Z₂;Xaa₃₁, Xaa₃₆, Xaa₃₇ and Xaa₃₈ being independently Pro homoproline,thioproline or N-methylalanine; and Z₂ being —OH or —NH₂; provided thatno more than three of Xaa₃, Xaa₅, Xaa₆, Xaa₈, Xaa₁₀, Xaa₁₁, Xaa₁₂,Xaa₁₃, Xaa₁₄, Xaa₁₅, Xaa₁₆, Xaa₁₇, Xaa₁₉, Xaa₂₀, Xaa₂₁, Xaa₂₄, Xaa₂₅,Xaa₂₆, Xaa₂₇ and Xaa₂₈ are Ala. Especially preferred compounds offormula (I) include those having the amino acid sequence of SEQ IDNOs:6-27 (Compounds 2-23).

According to an especially preferred aspect, provided are compounds ofcompound (I) where Xaa₁₄ is Leu, Ile, Val or pentylglycine, morepreferably Leu or pentylglycine, and Xaa₂₅ is Phe, Tyr ornaphthylalanine, more preferably Phe or naphthylalanine. These compoundswill be less susceptive to oxidative degration, both in vitro and invivo, as well as during synthesis of the compound.

Also within the scope of the present invention are narrower genera ofcompounds having peptides of various lengths, for example genera ofcompounds which do not include peptides having a length of 28, 29, or 30amino acid residues, respectively. Additionally, the present inventionincludes narrower genera of compounds having particular amino acidsequences, for example, compounds of the formula (I) (SEQ ID NO:4):

Xaa₁ Xaa₂ Xaa₃ Gly Xaa₅ Xaa₆ Xaa₇ Xaa₈ Xaa₉ Xaa₁₀ Xaa₁₁ Xaa₁₂ Xaa₁₃Xaa₁₄ Xaa₁₅ Xaa₁₆ Xaa₁₇ Ala Xaa₁₈ Xaa₁₉ Xaa₂₀ Xaa₂₁ Xaa₂₂ Xaa₂₃ Xaa₂₄Xaa₂₅ Xaa₂₆ Xaa₂₇ Xaa₂₈-Z₁; wherein Xaa₁ is His or Arg; Xaa₂ is Gly orAla; Xaa₃ is Asp or Glu; Xaa₅ is Ala or Thr; Xaa₆ is Ala, Phe ornaphthylalanine; Xaa₇ is Thr or Ser; Xaa₈ is Ala, Ser or Thr; Xaa₉ isAsp or Glu; Xaa₁₀ is Ala, Leu or pentylglycine; Xaa₁₁ is Ala or Ser;Xaa₁₂ is Ala or Lys; Xaa₁₃ is Ala or Gln; Xaa₁₄ is Ala, Leu orpentylglycine; Xaa₁₅ is Ala or Glu; Xaa₁₆ is Ala or Glu; Xaa₁₇ is Ala orGlu; Xaa₁₉ is Ala or Val; Xaa₂₀ is Ala or Arg; Xaa₂₁ is Ala or Leu;Xaa₂₂ is Phe or naphthylalanine; Xaa₂₃ is Ile, Val or tert-butylglycine;Xaa₂₄ is Ala, Glu or Asp; Xaa₂₅ is Ala, Trp, or Phe; Xaa₂₆ is Ala orLeu; Xaa₂₇ is Ala or Lys; Xaa₂₈ is Ala or Asn; Z₁ is —OH,       —NH₂,

Gly-Z₂, Gly Gly -Z₂, Gly Gly Xaa₃₁-Z₂, Gly Gly Xaa₃₁ Ser-Z₂, Gly GlyXaa₃₁ Ser Ser-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly-Z₂, Gly Gly Xaa₃₁ Ser SerGly Ala-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆-Z₂, Gly Gly Xaa₃₁ SerSer Gly Ala Xaa₃₆ Xaa₃₇-Z₂ or Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇Xaa₃₈- Z₂; Xaa₃₁, Xaa₃₆, Xaa₃₇ and Xaa₃₈ are independently selected fromthe group consisting of Pro, homo- proline, thioproline andN-methylylalanine; and Z₂ is —OH or —NH₂;provided that no more than three of Xaa₃, Xaa₅, Xaa₆, Xaa₈, Xaa₁₀,Xaa₁₁, Xaa₁₂, Xaa₁₃, Xaa₁₄, Xaa₁₅, Xaa₁₆, Xaa₁₇, Xaa₁₉, Xaa₂₀, Xaa₂₁,Xaa₂₄, Xaa₂₅, Xaa₂₆, Xaa₂₇ and Xaa₂₈ are Ala; and pharmaceuticallyacceptable salts thereof.

Also provided are compounds of the formula (II) (SEQ ID NO:66):

                  5                     10 Xaa₁ Xaa₂ Xaa₃ Gly Xaa₅ Xaa₆Xaa₇ Xaa₈ Xaa₉ Xaa₁₀ Xaa₁₁ Xaa₁₂ Xaa₁₃ Xaa₁₄ Xaa₁₅ Xaa₁₆ Xaa₁₇ Ala Xaa₁₉Xaa₂₀ Xaa₂₁ Xaa₂₂ Xaa₂₃ Xaa₂₄ Xaa₂₅ Xaa₂₆ X₁ -Z₁; wherein Xaa₁ is His,Arg or Tyr or 4-imidazopropionyl; Xaa₂ is Ser, Gly, Ala or Thr; Xaa₃ isAsp or Glu; Xaa₅ is Ala or Thr; Xaa₆ is Ala, Phe, Tyr ornaphthylalanine; Xaa₇ is Thr or Ser; Xaa₈ is Ala, Ser or Thr; Xaa₉ isAsp or Glu; Xaa₁₀ is Ala, Leu, Ile, Val, pentylglycine or Met; Xaa₁₁ isAla or Ser; Xaa₁₂ is Ala or Lys; Xaa₁₃ is Ala or Gln; Xaa₁₄ is Ala, Leu,Ile, pentylglycine, Val or Met; Xaa₁₅ is Ala or Glu; Xaa₁₆ is Ala orGlu; Xaa₁₇ is Ala or Glu; Xaa₁₉ is Ala or Val; Xaa₂₀ is Ala or Arg;Xaa₂₁ is Ala, Leu or Lys-NH^(ε)-R where R is Lys, Arg, C₁-C₁₀ straightchain or branched alkanoyl or cycloalkylalkanoyl; Xaa₂₂ is Phe, Tyr ornaphthylalanine; Xaa₂₃ is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met; Xaa₂₄ is Ala, Glu or Asp; Xaa₂₅ is Ala, Trp, Phe,Tyr or naphthylalanine; Xaa₂₆ is Ala or Leu; X₁ is Lys Asn, Asn Lys,Lys-NH^(ε)-R Asn, Asn Lys- NH^(ε)-R, Lys-NH^(ε)-R Ala, Ala Lys-NH^(ε)-Rwhere R is Lys, Arg, C₁-C₁₀ straight chain or branched alkanoyl orcyclo- alkylalkanoyl Z₁ is —OH, —NH₂,

Gly-Z₂, Gly Gly-Z₂, Gly Gly Xaa₃₁-Z₂, Gly Gly Xaa₃₁ Ser-Z₂, Gly GlyXaa₃₁ Ser Ser-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly-Z₂, Gly Gly Xaa₃₁ Ser SerGly Ala-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆-Z₂, Gly Gly Xaa₃₁ SerSer Gly Ala Xaa₃₆ Xaa₃₇-Z₂ or Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇Xaa₃₈- Z₂; wherein Xaa₃₁, Xaa₃₆, Xaa₃₇ and Xaa₃₈ are independentlyselected from the group consisting of Pro, homoproline, 3Hyp, 4Hyp,thioproline, N-alkylglycine, N-alkylpentylglycine and N-alkylalanine;and Z₂ is —OH or —NH₂;provided that no more than three of Xaa₃, Xaa₅, Xaa₆, Xaa₈, Xaa₁₀,Xaa₁₁, Xaa₁₂, Xaa₁₃, Xaa₁₄, Xaa₁₅, Xaa₁₆, Xaa₁₇, Xaa₁₉, Xaa₂₀, Xaa₂₁,Xaa₂₄, Xaa₂₅, and Xaa₂₆ are Ala. Also within the scope of the presentinvention are pharmaceutically acceptable salts of the compound offormula (II) and pharmaceutical compositions including said compoundsand salts thereof.

Preferred exendin agonist compounds of formula (II) include thosewherein Xaa₁ is His, Tyr or 4-imidazopropionyl. More preferably Xaa₁ isHis.

Preferred are those compounds of formula (II) wherein Xaa₁ is4-imidazopropionyl.

Preferred are those compounds of formula (II) wherein Xaa₂ is Gly.

Preferred compounds of formula (II) are those wherein Xaa₁₄ is Leu,pentylglycine or Met.

Preferred compounds of formula (II) are those wherein Xaa₂₅ is Trp orPhe.

According to one aspect, preferred are compounds of formula (II) whereinXaa₆ is Phe or naphthylalanine; and Xaa₂₂ is Phe or naphthylalanine; andXaa₂₃ is Ile or Val. More preferably, Z₁ is —NH₂. According to oneaspect, especially preferred are such compounds of formula (II) whereinXaa₃₁, Xaa₃₆, Xaa₃₇ and Xaa₃₈ are independently selected from the groupconsisting of Pro, homoproline, thioproline and N-alkylalanine. Morepreferds, Z₂ is —NH₂.

Preferred compounds of formula (II) include those wherein X₁ is Lys Asn,Lys-NH^(ε)—R Asn, or Lys-NH^(ε)—R Ala where R is Lys, Arg, C₁-C₁₀straight chain or branched alkanoyl. Preferred compounds of formula (II)include Compound Nos. 62-69 (SEQ ID NOs:67-74).

The compounds referenced above form salts with various inorganic andorganic acids and bases. Such salts include salts prepared with organicand inorganic acids, for example, HCl, HBr, H₂SO₄, H₃PO₄,trifluoroacetic acid, acetic acid, formic acid, methanesulfonic acid,toluenesulfonic acid, maleic acid, fumaric acid and camphorsulfonicacid. Salts prepared with bases include ammonium salts, alkali metalsalts, e.g. sodium and potassium salts, and alkali earth salts, e.g.calcium and magnesium salts. Acetate, hydrochloride, andtrifluoroacetate salts are preferred. The salts may be formed byconventional means, as by reacting the free acid or base forms of theproduct with one or more equivalents of the appropriate base or acid ina solvent or medium in which the salt is insoluble, or in a solvent suchas water which is then removed in vacuo or by freeze-drying or byexchanging the ions of an existing salt for another ion on a suitableion exchange resin.

Utility

The compounds described above are useful in view of theirpharmacological properties. In particular, the compounds of theinvention are exendin agonists, and possess activity as agents toregulate gastric motility and to slow gastric emptying, as evidenced bythe ability to reduce post-prandial glucose levels in mammals.

The compounds of the present invention are useful in in vitro and invivo scientific methods for investigation of exendins and exendinagonists for example in methods such as those described in Examples A-Ebelow.

Preparation of Compounds

The compounds of the present invention may be prepared using standardsolid-phase peptide synthesis techniques and preferably an automated orsemiautomated peptide synthesizer. Typically, using such techniques, anα-N-carbamoyl protected amino acid and an amino acid attached to thegrowing peptide chain on a resin are coupled at room temperature in aninert solvent such as dimethylformamide, N-methylpyrrolidinone ormethylene chloride in the presence of coupling agents such asdicyclohexylcarbodiimide and 1-hydroxybenzotriazole in the presence of abase such as diisopropylethylamine. The α-N-carbamoyl protecting groupis removed from the resulting peptide-resin using a reagent such astrifluoroacetic acid or piperidine, and the coupling reaction repeatedwith the next desired N-protected amino acid to be added to the peptidechain. Suitable N-protecting groups are well known in the art, witht-butyloxycarbonyl (tBoc) and fluorenylmethoxycarbonyl (Fmoc) beingpreferred herein.

The solvents, amino acid derivatives and 4-methylbenzhydryl-amine resinused in the peptide synthesizer may be purchased from Applied BiosystemsInc. (Foster City, Calif.). The following side-chain protected aminoacids may be purchased from Applied Biosystems, Inc.: Boc-Arg(Mts),Fmoc-Arg(Pmc), Boc-Thr(Bzl), Fmoc-Thr(t-Bu), Boc-Ser(Bzl),Fmoc-Ser(t-Bu), Boc-Tyr(BrZ), Fmoc-Tyr(t-Bu), Boc-Lys(Cl-Z),Fmoc-Lys(Boc), Boc-Glu(Bzl), Fmoc-Glu(t-Bu), Fmoc-His(Trt),Fmoc-Asn(Trt), and Fmoc-Gln(Trt). Boc-His(BOM) may be purchased fromApplied Biosystems, Inc. or Bachem Inc. (Torrance, Calif.). Anisole,dimethylsulfide, phenol, ethanedithiol, and thioanisole may be obtainedfrom Aldrich Chemical Company (Milwaukee, Wis.). Air Products andChemicals (Allentown, Pa.) supplies HF. Ethyl ether, acetic acid andmethanol may be purchased from Fisher Scientific (Pittsburgh, Pa.).

Solid phase peptide synthesis may be carried out with an automaticpeptide synthesizer (Model 430A, Applied Biosystems Inc., Foster City,Calif.) using the NMP/HOBt (Option 1) system and tBoc or Fmoc chemistry(see, Applied Biosystems User's Manual for the ABI 430A PeptideSynthesizer, Version 1.3B Jul. 1, 1988, section 6, pp. 49-70, AppliedBiosystems, Inc., Foster City, Calif.) with capping. Boc-peptide-resinsmay be cleaved with HF (−5° C. to 0° C., 1 hour). The peptide may beextracted from the resin with alternating water and acetic acid, and thefiltrates lyophilized. The Fmoc-peptide resins may be cleaved accordingto standard methods (Introduction to Cleavage Techniques, AppliedBiosystems, Inc., 1990, pp. 6-12). Peptides may be also be assembledusing an Advanced Chem Tech Synthesizer (Model MPS 350, Louisville,Ky.).

Peptides may be purified by RP-HPLC (preparative and analytical) using aWaters Delta Prep 3000 system. A C4, C8 or C18 preparative column (10μ,2.2×25 cm; Vydac, Hesperia, Calif.) may be used to isolate peptides, andpurity may be determined using a C4, C8 or C18 analytical column (5 u,0.46×25 cm; Vydac). Solvents (A=0.1% TFA/water and B=0.1% TFA/CH₃CN) maybe delivered to the analytical column at a flowrate of 1.0 ml/min and tothe preparative column at 15 ml/min. Amino acid analyses may beperformed on the Waters Pico Tag system and processed using the Maximaprogram. Peptides may be hydrolyzed by vapor-phase acid hydrolysis (115°C., 20-24 h). Hydrolysates may be derivatized and analyzed by standardmethods (Cohen, et al., The Pico Tag Method: A Manual of AdvancedTechniques for Amino Acid Analysis, pp. 11-52, Millipore Corporation,Milford, Mass. (1989)). Fast atom bombardment analysis may be carriedout by M-Scan, Incorporated (West Chester, Pa.). Mass calibration may beperformed using cesium iodide or cesium iodide/glycerol. Plasmadesorption ionization analysis using time of flight detection may becarried out on an Applied Biosystems Bio-Ion 20 mass spectrometer.Electrospray mass spectroscopy may be carried and on a VG-Trio machine.

Peptide compounds useful in the invention may also be prepared usingrecombinant DNA techniques, using methods now known in the art. See,e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual, 2d Ed.,Cold Spring Harbor (1989). Non-peptide compounds useful in the presentinvention may be prepared by art-known methods.

Formulation and Administration

Compounds of the invention are useful in view of their exendin-likeeffects, and may conveniently be provided in the form of formulationssuitable for parenteral (including intravenous, intramuscular andsubcutaneous) or nasal, sublingual, buccal or oral administration. Insome cases, it will be convenient to provide an exendin agonist andanother anti-gastric-emptying agent, such as glucagon, an amylin, or anamylin agonist, in a single composition or solution for administrationtogether. In other cases, it may be more advantageous to administeranother anti-emptying agent separately from said exendin agonist. In yetother cases, it may be beneficial to provide an exendin agonist eitherco-formulated or separately with other glucose lowering agents such asinsulin. A suitable administration format may best be determined by amedical practitioner for each patient individually. Suitablepharmaceutically acceptable carriers and their formulation are describedin standard formulation treatises, e.g., Remington's PharmaceuticalSciences by E. W. Martin. See also Wang, Y. J. and Hanson, M. A.“Parenteral Formulations of Proteins and Peptides: Stability andStabilizers,” Journal of Parenteral Science and Technology, TechnicalReport No. 10, Supp. 42:2 S (1988).

Compounds useful in the invention can be provided as parenteralcompositions for injection or infusion. They can, for example, besuspended in an inert oil, suitably a vegetable oil such as sesame,peanut, olive oil, or other acceptable carrier. Preferably, they aresuspended in an aqueous carrier, for example, in an isotonic buffersolution at a pH of about 5.6 to 7.4. These compositions may besterilized by conventional sterilization techniques, or may be sterilefiltered. The compositions may contain pharmaceutically acceptableauxiliary substances as required to approximate physiologicalconditions, such as pH buffering agents. Useful buffers include forexample, sodium acetate/acetic acid buffers. A form of repository or“depot” slow release preparation may be used so that therapeuticallyeffective amounts of the preparation are delivered into the bloodstreamover many hours or days following transdermal injection or other form ofdelivery.

The desired isotonicity may be accomplished using sodium chloride orother pharmaceutically acceptable agents such as dextrose, boric acid,sodium tartrate, propylene glycol, polyols (such as mannitol andsorbitol), or other inorganic or organic solutes. Sodium chloride ispreferred particularly for buffers containing sodium ions.

The claimed compounds can also be formulated as pharmaceuticallyacceptable salts (e.g., acid addition salts) and/or complexes thereof.Pharmaceutically acceptable salts are non-toxic salts at theconcentration at which they are administered. The preparation of suchsalts can facilitate the pharmacological use by altering thephysical-chemical characteristics of the composition without preventingthe composition from exerting its physiological effect. Examples ofuseful alterations in physical properties include lowering the meltingpoint to facilitate transmucosal administration and increasing thesolubility to facilitate the administration of higher concentrations ofthe drug.

Pharmaceutically acceptable salts include acid addition salts such asthose containing sulfate, hydrochloride, phosphate, sulfamate, acetate,citrate, lactate, tartrate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.Pharmaceutically acceptable salts can be obtained from acids such ashydrochloric acid, sulfuric acid, phosphoric acid, sulfamic acid, aceticacid, citric acid, lactic acid, tartaric acid, malonic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, cyclohexylsulfamic acid, and quinic acid. Suchsalts may be prepared by, for example, reacting the free acid or baseforms of the product with one or more equivalents of the appropriatebase or acid in a solvent or medium in which the salt is insoluble, orin a solvent such as water which is then removed in vacuo or byfreeze-drying or by exchanging the ions of an existing salt for anotherion on a suitable ion exchange resin.

Carriers or excipients can also be used to facilitate administration ofthe compound. Examples of carriers and excipients include calciumcarbonate, calcium phosphate, various sugars such as lactose, glucose,or sucrose, or types of starch, cellulose derivatives, gelatin,vegetable oils, polyethylene glycols and physiologically compatiblesolvents. The compositions or pharmaceutical composition can beadministered by different routes including intravenously,intraperitoneal, subcutaneous, and intramuscular, orally, topically,transdermally, buccally or transmucosally.

If desired, solutions of the above compositions may be thickened with athickening agent such as methyl cellulose. They may be prepared inemulsified form, either water in oil or oil in water. Any of a widevariety of pharmaceutically acceptable emulsifying agents may beemployed including, for example, acacia powder, a non-ionic surfactant(such as a Tween), or an ionic surfactant (such as alkali polyetheralcohol sulfates or sulfonates, e.g., a Triton).

Compositions useful in the invention are prepared by mixing theingredients following generally accepted procedures. For example, theselected components may be simply mixed in a blender or other standarddevice to produce a concentrated mixture which may then be adjusted tothe final concentration and viscosity by the addition of water orthickening agent and possibly a buffer to control pH or an additionalsolute to control tonicity.

For use by the physician, the compounds will be provided in dosage unitform containing an amount of an exendin agonist, with or without anotheranti-emptying agent. Therapeutically effective amounts of an exendinagonist for use in the control of gastric emptying and in conditions inwhich gastric emptying is beneficially slowed or regulated are thosethat decrease post-prandial blood glucose levels, preferably to no morethan about 8 or 9 mM or such that blood glucose levels are reduced asdesired. In diabetic or glucose intolerant individuals, plasma glucoselevels are higher than in normal individuals. In such individuals,beneficial reduction or “smoothing” of post-prandial blood glucoselevels, may be obtained. As will be recognized by those in the field, aneffective amount of therapeutic agent will vary with many factorsincluding the patient's physical condition, the blood sugar level orlevel of inhibition of gastric emptying to be obtained, and otherfactors.

Such pharmaceutical compositions are useful in causing gastrichypomotility in a subject and may be used as well in other disorderswhere gastric motility is beneficially reduced.

The effective daily anti-emptying dose of the compounds will typicallybe in the range of 0.001 or 0.005 to about 5 mg/day, preferably about0.01 or 0.05 to 2 mg/day and more preferably about 0.05 or 0.1 to 1mg/day, for a 70 kg patient. The exact dose to be administered isdetermined by the attending clinician and is dependent upon where theparticular compound lies within the above quoted range, as well as uponthe age, weight and condition of the individual. Administration shouldbegin at the first sign of symptoms or shortly after diagnosis ofdiabetes mellitus. Administration may be by injection, preferablysubcutaneous or intramuscular, or by other routes for example, by oral,nasal, sublingual or buccal administration. For oral, nasal or buccaldosages should be increased to about 5-10 fold over injection dosages.

Generally, in treating or preventing elevated, inappropriate, orundesired post-prandial blood glucose levels, the compounds of thisinvention may be administered to patients in need of such treatment in adosage ranges similar to those given above, however, the compounds areadministered more frequently, for example, one, two, or three times aday.

The optimal formulation and mode of administration of compounds of thepresent application to a patient depend on factors known in the art suchas the particular disease or disorder, the desired effect, and the typeof patient. While the compounds will typically be used to treat humanpatients, they may also be used to treat similar or identical diseasesin other vertebrates such as other primates, farm animals such as swine,cattle and poultry, and sports animals and pets such as horses, dogs andcats.

To assist in understanding the present invention the following Examplesare included which describe the results of a series of experiments. Theexperiments relating to this invention should not, of course, beconstrued as specifically limiting the invention and such variations ofthe invention, now known or later developed, which would be within thepurview of one skilled in the art are considered to fall within thescope of the invention as described herein and hereinafter claimed.

Example 1 Preparation of Compound 1

[SEQ. ID. NO. 5] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly-NH₂

The above amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.). In general, single-coupling cycles were usedthroughout the synthesis and Fast Moc (HBTU activation) chemistry wasemployed. Deprotection (Fmoc group removal) of the growing peptide chainwas achieved using piperidine. Final deprotection of the completedpeptide resin was achieved using a mixture of triethylsilane (0.2 mL),ethanedithiol (0.2 mL), anisole (0.2 mL), water (0.2 mL) andtrifluoroacetic acid (15 mL) according to standard methods (Introductionto Cleavage Techniques, Applied Biosystems, Inc.) The peptide wasprecipitated in ether/water (50 mL) and centrifuged. The precipitate wasreconstituted in glacial acetic acid and lyophilized. The lyophilizedpeptide was dissolved in water). Crude purity was about 75%.

Used in purification steps and analysis were Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN).

The solution containing peptide was applied to a preparative C-18 columnand purified (10% to 40% Solvent B in Solvent A over 40 minutes). Purityof fractions was determined isocratically using a C-18 analyticalcolumn. Pure fractions were pooled furnishing the above-identifiedpeptide. Analytical RP-HPLC (gradient 30% to 50% Solvent B in Solvent Aover 30 minutes) of the lyophilized peptide gave product peptide havingan observed retention time of 18.9 minutes. Electrospray MassSpectrometry (M): calculated 3408.0; found 3408.9.

Example 2 Preparation of Compound 2

[SEQ. ID. NO. 6] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 40% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 17.9 minutes. Electrospray Mass Spectrometry (M): calculated3294.7; found 3294.8.

Example 3 Preparation of Compound 3

[SEQ. ID. NO. 7] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 29% to 36% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 20.7 minutes. Electrospray Mass Spectrometry (M): calculated3237.6; found 3240.

Example 4 Preparation of Compound 4

[SEQ. ID. NO. 8] His Ala Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 36% to 46% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 15.2 minutes. Electrospray Mass Spectrometry (M): calculated3251.6; found 3251.5.

Example 5 Preparation of Compound 5

[SEQ. ID. NO. 9] His Gly Glu Gly Ala Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 36% to 46% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 13.1 minutes. Electrospray Mass Spectrometry (M): calculated3207.6; found 3208.3.

Example 6 Preparation of Compound 6

[SEQ. ID. NO. 10] His Gly Glu Gly Thr Ala Thr Ser Asp Leu Ser Lys GlnLeu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 35% to 45% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 12.8 minutes. Electrospray Mass Spectrometry (M): calculated3161.5; found 3163.

Example 7 Preparation of Compound 7

[SEQ. ID. NO. 11] His Gly Glu Gly Thr Phe Thr Ala Asp Leu Ser Lys GlnLeu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 36% to 46% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 15.2 minutes. Electrospray Mass Spectrometry (M): calculated3221.6; found 3222.7.

Example 8 Preparation of Compound 8

[SEQ. ID. NO. 12] His Gly Glu Gly Thr Phe Thr Ser Asp Ala Ser Lys GlnLeu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 34% to 44% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 14.3 minutes. Electrospray Mass Spectrometry (M): calculated3195.5; found 3199.4.

Example 9 Preparation of Compound 9

[SEQ. ID. NO. 13] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ala Lys GlnLeu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 38% to 48% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 15.7 minutes. Electrospray Mass Spectrometry (M): calculated3221.6; found 3221.6.

Example 10 Preparation of Compound 10

[SEQ. ID. NO. 14] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Ala GlnLeu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 38% to 48% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 18.1 minutes. Electrospray Mass Spectrometry (M): calculated3180.5; found 3180.9.

Example 11 Preparation of Compound 11

[SEQ. ID. NO. 15] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys AlaLeu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 36% to 46% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 17.0 minutes. Electrospray Mass Spectrometry (M): calculated3180.6; found 3182.8.

Example 12 Preparation of Compound 12

[SEQ. ID. NO. 16] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnAla Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 32% to 42% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 14.9 minutes. Electrospray Mass Spectrometry (M): calculated3195.5; found 3195.9.

Example 13 Preparation of Compound 13

[SEQ. ID. NO. 17] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnLeu Ala Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 37% to 47% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 17.9 minutes. Electrospray Mass Spectrometry (M): calculated3179.6; found 3179.0.

Example 14 Preparation of Compound 14

[SEQ. ID. NO. 18] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnLeu Glu Ala Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 37% to 47% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 14.3 minutes. Electrospray Mass Spectrometry (M): calculated3179.6; found 3180.0.

Example 15 Preparation of Compound 15

[SEQ. ID. NO. 19] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnLeu Glu Glu Ala Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 37% to 47% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 13.7 minutes. Electrospray Mass Spectrometry (M): calculated3179.6; found 3179.0.

Example 16 Preparation of Compound 16

[SEQ. ID. NO. 20] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnLeu Glu Glu Glu Ala Ala Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 35% to 45% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 14.0 minutes. Electrospray Mass Spectrometry (M): calculated3209.6; found 3212.8.

Example 17 Preparation of Compound 17

[SEQ. ID. NO. 21] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnLeu Glu Glu Glu Ala Val Ala Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 38% to 48% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 14.3 minutes. Electrospray Mass Spectrometry (M): calculated3152.5; found 3153.5.

Example 18 Preparation of Compound 18

[SEQ. ID. NO. 22] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnLeu Glu Glu Glu Ala Val Arg Ala Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 35% to 45% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 12.1 minutes. Electrospray Mass Spectrometry (M): calculated3195.5; found 3197.7.

Example 19 Preparation of Compound 19

[SEQ. ID. NO. 23] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnLeu Glu Glu Glu Ala Val Arg Leu Phe Ile Ala Phe Leu Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 38% to 48% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 10.9 minutes. Electrospray Mass Spectrometry (M): calculated3179.6; found 3180.5.

Example 20 Preparation of Compound 20

[SEQ. ID. NO. 24] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnLeu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Ala Leu Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 32% to 42% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 17.5 minutes. Electrospray Mass Spectrometry (M): calculated3161.5; found 3163.0.

Example 21 Preparation of Compound 21

[SEQ. ID. NO. 25] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnLeu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Ala Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 32% to 42% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 19.5 minutes. Electrospray Mass Spectrometry (M): calculated3195.5; found 3199.

Example 22 Preparation of Compound 22

[SEQ. ID. NO. 26] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnLeu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Ala Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 38% to 48% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 14.5 minutes. Electrospray Mass Spectrometry (M): calculated3180.5; found 3183.7.

Example 23 Preparation of Compound 23

[SEQ. ID. NO. 27] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnLeu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Ala-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 34% to 44% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 22.8 minutes. Electrospray Mass Spectrometry (M): calculated3194.6; found 3197.6.

Example 24 Preparation of Compound 24

[SEQ. ID. NO. 28] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnMet Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly ProSer Ser Gly Ala Pro Pro Pro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4099.6.

Example 25 Preparation of Compound 25

[SEQ. ID. NO. 29] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnLeu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly ProSer Ser Gly Ala Pro Pro Pro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4042.5.

Example 26 Preparation of Compound 26

[SEQ. ID. NO. 30] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnMet Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly ProSer Ser Gly Ala Pro Pro-NH₂

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4002.4

Example 27 Preparation of Compound 27

[SEQ. ID. NO. 31] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnLeu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly ProSer Ser Gly Ala Pro Pro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3945.4.

Example 28 Preparation of Compound 28

[SEQ. ID. NO. 32] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnMet Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly ProSer Ser Gly Ala Pro- NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3905.3.

Example 29 Preparation of Compound 29

[SEQ. ID. NO. 33] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnLeu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly ProSer Ser Gly Ala Pro- NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3848.2.

Example 30 Preparation of Compound 30

[SEQ. ID. NO. 34] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnMet Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly ProSer Ser Gly Ala-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3808.2.

Example 31 Preparation of Compound 31

[SEQ. ID. NO. 35] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnLeu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly ProSer Ser Gly Ala-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3751.1.

Example 32 Preparation of Compound 32

[SEQ. ID. NO. 36] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnMet Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly ProSer Ser Gly-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3737.1.

Example 33 Preparation of Compound 33

[SEQ. ID. NO. 37] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnLeu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly ProSer Ser Gly-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3680.1.

Example 34 Preparation of Compound 34

[SEQ. ID. NO. 38] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnMet Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly ProSer Ser-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3680.1

Example 35 Preparation of Compound 35

[SEQ. ID. NO. 39] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnLeu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly ProSer Ser-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3623.0.

Example 36 Preparation of Compound 36

[SEQ. ID. NO. 40] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnMet Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly ProSer-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3593.0

Example 37 Preparation of Compound 37

[SEQ. ID. NO. 41] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnLeu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly ProSer-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3535.9

Example 38 Preparation of Compound 38

[SEQ. ID. NO. 42] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnMet Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly GlyPro-NH₂

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3505.9.

Example 39 Preparation of Compound 39

[SEQ. ID. NO. 43] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnLeu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly GlyPro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3448.8.

Example 40 Preparation of Compound 40

[SEQ. ID. NO. 44] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnLeu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly-NH₂

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3351.7.

Example 41 Preparation of Compound 41

[SEQ. ID. NO. 45] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnMet Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly-NH₂

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3351.8.

Example 42 Preparation of Compound 42

[SEQ. ID. NO. 46] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnLeu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3294.7.

Example 43 Preparation of Compound 43

[SEQ. ID. NO. 47] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnMet Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly tProSer Ser Gly Ala tPro tPro tPro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Double couplings are requiredat residues 37, 36 and 31. Used in analysis are Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30%to 60% Solvent B in Solvent A over 30 minutes) of the lyophilizedpeptide is then carried out to determine the retention time of theproduct peptide. Electrospray Mass Spectrometry (M): calculated 4197.1.

Example 44 Preparation of Compound 44

[SEQ. ID. NO. 48] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnMet Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly ProSer Ser Gly Ala tPro tPro tPro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Double couplings are requiredat residues 37, 36 and 31. Used in analysis are Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30%to 60% Solvent B in Solvent A over 30 minutes) of the lyophilizedpeptide is then carried out to determine the retention time of theproduct peptide. Electrospray Mass Spectrometry (M): calculated 4179.1.

Example 45 Preparation of Compound 45

[SEQ. ID. NO. 49] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnMet Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly GlyNMeala Ser Ser Gly Ala Pro Pro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Double couplings are requiredat residues 36 and 31. Used in analysis are Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30%to 60% Solvent B in Solvent A over 30 minutes) of the lyophilizedpeptide is then carried out to determine the retention time of theproduct peptide. Electrospray Mass Spectrometry (M): calculated 3948.3.

Example 46 Preparation of Compound 46

[SEQ. ID. NO. 50] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnMet Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly GlyNMeala Ser Ser Gly Ala NMeala Nmeala-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Double couplings are requiredat residues 36 and 31. Used in analysis are Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30%to 60% Solvent B in Solvent A over 30 minutes) of the lyophilizedpeptide is then carried out to determine the retention time of theproduct peptide. Electrospray Mass Spectrometry (M): calculated 3840.1.

Example 47 Preparation of Compound 47

[SEQ. ID. NO. 51] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnMet Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly hProSer Ser Gly Ala hPro hPro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Double couplings are requiredat residues 36 and 31. Used in analysis are Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30%to 60% Solvent B in Solvent A over 30 minutes) of the lyophilizedpeptide is then carried out to determine the retention time of theproduct peptide. Electrospray Mass Spectrometry (M): calculated 4050.1.

Example 48 Preparation of Compound 48

[SEQ. ID. NO. 52] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnMet Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly hProSer Ser Gly Ala hPro- NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. A double coupling is requiredat residue 31. Used in analysis are Solvent A (0.1% TFA in water) andSolvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30% to 60%Solvent B in Solvent A over 30 minutes) of the lyophilized peptide isthen carried out to determine the retention time of the product peptide.Electrospray Mass Spectrometry (M): calculated 3937.1

Example 49 Preparation of Compound 49

[SEQ. ID. NO. 53] Arg Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnMet Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly ProSer Ser Gly Ala-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3827.2.

Example 50 Preparation of Compound 50

[SEQ. ID. NO. 54] His Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnMet Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3394.8.

Example 51 Preparation of Compound 51

[SEQ. ID. NO. 55] His Gly Glu Gly Thr Naphthylala Thr Ser Asp Leu SerLys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3289.5.

Example 52 Preparation of Compound 52

[SEQ. ID. NO. 56] His Gly Glu Gly Thr Phe Ser Ser Asp Leu Ser Lys GlnMet Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3280.7.

Example 53 Preparation of Compound 53

[SEQ. ID. NO. 57] His Gly Glu Gly Thr Phe Ser Thr Asp Leu Ser Lys GlnMet Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3294.7.

Example 54 Preparation of Compound 54

[SEQ. ID. NO. 58] His Gly Glu Gly Thr Phe Thr Ser Glu Leu Ser Lys GlnMet Ala Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3250.7.

Example 55 Preparation of Compound 55

[SEQ. ID. NO. 59] His Gly Glu Gly Thr Phe Thr Ser Asp pentylgly Ser LysGln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3253.5.

Example 56 Preparation of Compound 56

[SEQ. ID. NO. 60] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnLeu Glu Glu Glu Ala Val Arg Leu Naphthylala Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3289.5.

Example 57 Preparation of Compound 57

[SEQ. ID. NO. 61] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnMet Glu Glu Glu Ala Val Arg Leu Phe tButylgly Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3183.4.

Example 58 Preparation of Compound 58

[SEQ. ID. NO. 62] His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnLeu Glu Glu Glu Ala Val Arg Leu Phe Ile Asp Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3237.6.

Example 59 Preparation of Compound 59

[SEQ. ID. NO. 63] His Gly Glu Gly Thr Phe Thr Ser Asp Ala Ser Lys GlnLeu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly ProSer Ser-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3637.9.

Example 60 Preparation of Compound 60

[SEQ. ID. NO. 64] His Gly Glu Gly Thr Phe Thr Ser Asp Ala Ser Lys GlnMet Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3309.7.

Example 61 Preparation of Compound 61

[SEQ. ID. NO. 65] His Gly Glu Gly Thr Phe Thr Ser Asp Ala Ser Lys GlnMet Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly hProSer Ser Gly Ala hPro hPro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Double couplings are requiredat residues 36 and 31. Used in analysis are Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30%to 60% Solvent B in Solvent A over 30 minutes) of the lyophilizedpeptide is then carried out to determine the retention time of theproduct peptide. Electrospray Mass Spectrometry (M): calculated 3711.1.

Example 62 Preparation of Peptide Having SEQ. ID. NO. 67

Compound 62, 4-imidazolylpropionyl-Gly Glu Gly Thr Phe Thr Ser Asp LeuSer Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp LeuLys-NH^(ε)octanoyl Asn-NH₂ [SEQ. ID. NO. 67], is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Fmoc-Lys-NH^(ε)octanoyl acid isused for coupling at position 27. Instead of using a protected aminoacid for the final coupling at position 1,4-imidazolylpropionic acid iscoupled directly to the N-terminus of residues 2-28 on the resin. Usedin analysis are Solvent A (0.1% TFA in water) and Solvent B (0.1% TFA inACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent Aover 30 minutes) of the lyophilized peptide is then carried out todetermine the retention time of the product peptide. Electrospray MassSpectrometry (M): calculated 3405.0

Example 63 Preparation of Peptide Having SEQ. ID. NO. 68

Compound 63, 4-imidazolylpropionyl-Gly Glu Gly Thr Phe Thr Ser Asp LeuSer Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe LeuLys-NH^(ε)octanoyl Asn-NH₂ [SEQ. ID. NO. 68], is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Fmoc-Lys-NH^(ε)octanoyl acid isused for coupling at position 27. Instead of using a protected aminoacid for the final coupling at position 1, 4-imidazolylpropionic acid iscoupled directly to the N-terminus of residues 2-28 on the resin. Usedin analysis are Solvent A (0.1% TFA in water) and Solvent B (0.1% TFA inACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent Aover 30 minutes) of the lyophilized peptide is then carried out todetermine the retention time of the product peptide. Electrospray MassSpectrometry (M): calculated 3347.9

Example 64 Preparation of Peptide Having SEQ. ID. NO. 69

Compound 64, 4-imidazolylpropionyl-Gly Glu Gly Thr Phe Thr Ser Asp LeuSer Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp LeuLys-NH^(ε)octanoyl Asn Gly Gly-NH₂ [SEQ. ID. NO. 69], is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Fmoc-Lys-NH^(ε)octanoyl acid isused for coupling at position 27. Instead of using a protected aminoacid for the final coupling at position 1, 4-imidazolylpropionic acid iscoupled directly to the N-terminus of residues 2-30 on the resin. Usedin analysis are Solvent A (0.1% TFA in water) and Solvent B (0.1% TFA inACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent Aover 30 minutes) of the lyophilized peptide is then carried out todetermine the retention time of the product peptide. Electrospray MassSpectrometry (M): calculated 3519.0

Example 65 Preparation of Peptide Having SEQ. ID. NO. 70

Compound 65, 4-imidazolylpropionyl-Gly Glu Gly Thr Phe Thr Ser Asp LeuSer Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe LeuLys-NH^(ε)octanoyl Asn Gly Gly-NH₂ [SEQ. ID. NO. 70], is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Fmoc-Lys-NH^(ε)octanoyl acid isused for coupling at position 27. Instead of using a protected aminoacid for the final coupling at position 1, 4-imidazolylpropionic acid iscoupled directly to the N-terminus of residues 2-30 on the resin. Usedin analysis are Solvent A (0.1% TFA in water) and Solvent B (0.1% TFA inACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent Aover 30 minutes) of the lyophilized peptide is then carried out todetermine the retention time of the product peptide. Electrospray MassSpectrometry (M): calculated 3451.9

Example 66 Preparation of Peptide Having SEQ. ID. NO. 71

Compound 66, 4-imidazolylpropionyl-Gly Glu Gly Thr Phe Thr Ser Asp LeuSer Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu AsnLys-NH^(ε)octanoyl-NH₂ [SEQ. ID. NO. 71], is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Fmoc-Lys-NH^(ε)octanoyl acid isused for the initial coupling onto the resin at position 28. Instead ofusing a protected amino acid for the final coupling at position 1,4-imidazolylpropionic acid is coupled directly to the N-terminus ofprotected residues 2-28 on the resin. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3405.0

Example 67 Preparation of Peptide Having SEQ. ID. NO. 72

Compound 67, 4-imidazolylpropionyl-Gly Glu Gly Thr Phe Thr Ser Asp LeuSer Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu AsnLys-NH^(ε)octanoyl-NH₂ [SEQ. ID. NO. 72], is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Fmoc-Lys-NH^(ε)octanoyl acid isused for the initial coupling onto the resin at position 28. Instead ofusing a protected amino acid for the final coupling at position 1,4-imidazolylpropionic acid is coupled directly to the N-terminus ofresidues 2-28 on the resin. Used in analysis are Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30%to 60% Solvent B in Solvent A over 30 minutes) of the lyophilizedpeptide is then carried out to determine the retention time of theproduct peptide. Electrospray Mass Spectrometry (M): calculated 3347.9

Example 68 Preparation of Peptide Having SEQ. ID. NO. 73

Compound 68, 4-imidazolylpropionyl-Gly Glu Gly Thr Phe Thr Ser Asp LeuSer Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu AsnLys-NH^(ε)octanoyl Gly Gly-NH₂ [SEQ. ID. NO. 73], is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Fmoc-Lys-NH^(ε)octanoyl acid isused for coupling at position 28. Instead of using a protected aminoacid for the final coupling at position 1, 4-imidazolylpropionic acid iscoupled directly to the N-terminus of protected residues 2-30 on theresin. Used in analysis are Solvent A (0.1% TFA in water) and Solvent B(0.1% TFA in ACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B inSolvent A over 30 minutes) of the lyophilized peptide is then carriedout to determine the retention time of the product peptide. ElectrosprayMass Spectrometry (M): calculated 3519.0

Example 69 Preparation of Peptide Having SEQ. ID. NO. 74

Compound 69, 4-imidazolylpropionyl-Gly Glu Gly Thr Phe Thr Ser Asp LeuSer Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu AsnLys-NH^(ε)octanoyl Gly Gly-NH₂ [SEQ. ID. NO. 74], is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Fmoc-Lys-NH^(ε)octanoyl acid isused for coupling at position 28. Instead of using a protected aminoacid for the final coupling at position 1, 4-imidazolylpropionic acid iscoupled directly to the N-terminus of residues 2-30 on the resin. Usedin analysis are Solvent A (0.1% TFA in water) and Solvent B (0.1% TFA inACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent Aover 30 minutes) of the lyophilized peptide is then carried out todetermine the retention time of the product peptide. Electrospray MassSpectrometry (M): calculated 3451.9

Example 70 Preparation of C-Terminal Carboxylic Acid PeptidesCorresponding to the Above C-Terminal Amide Sequences for Compounds 1-3,30-37, 40-42, 49-58 and 62-69

Compounds 1-23, 30-37, 40-42, 49-58 and 62-69 [SEQ. ID. NOS. 5-27,34-41, 44-46, 53-62 and 67-74] are assembled on the so called Wang resin(p-alkoxybenzylalcohol resin (Bachem, 0.54 mmole/g)) usingFmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from theresin, deprotected and purified in a similar way to Compound 1. Used inanalysis are Solvent A (0.1% TFA in water) and Solvent B (0.1% TFA inACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent Aover 30 minutes) of the lyophilized peptide is then carried out todetermine the retention time of the product peptide. Electrospray MassSpectrometry provides an experimentally determined (M).

Example 71 Preparation of C-Terminal Carboxylic Acid PeptidesCorresponding to the Above C-Terminal Amide Sequences for Compounds24-29, 38, 39 and 43-48

Compounds 24-29, 38, 39, and 43-48 [SEQ. ID. NOS. 28-33, 42, 43 and47-52] are assembled on the 2-chlorotritylchloride resin (200-400 mesh),2% DVB (Novabiochem, 0.4-1.0 mmole/g)) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry provides anexperimentally determined (M).

Examples A to E Reagents Used

GLP-1(7-36) [NH₂] was purchased from Bachem (Torrance, Calif.). Allother peptides were prepared using synthesis methods such as thosedescribed therein. All chemicals were of the highest commercial grade.The cAMP SPA immunoassay was purchased from Amersham. The radioligandswere purchased from New England Nuclear (Boston, Mass.). RINm5f cells(American Type Tissue Collection, Rockville, Md.) were grown in DME/F12medium containing 10% fetal bovine serum and 2 mM L-glutamine. Cellswere grown at 37° C. and 5% CO₂/95% humidified air and medium wasreplaced every 2 to 3 days. Cells were grown to confluence thenharvested and homogenized using on a Polytron homogenizer. Cellhomogenates were stored frozen at −70° C. until used.

Example A GLP-1 Receptor Binding Studies

Receptor binding was assessed by measuring displacement of [¹²⁵I]GLP-1or [¹²⁵I]exendin(9-39) from RINm5f membranes. Assay buffer contained 5μg/ml bestatin, 1 μg/ml phosphoramidon, 1 mg/ml bovine serum albumin(fraction V), 1 mg/ml bacitracin, and 1 mM MgCl₂ in 20 mM HEPES, pH 7.4.To measure binding, 30 μg membrane protein (Bradford protein assay) wasresuspended in 200 μl assay buffer and incubated with 60 pM [¹²⁵I]GLP-1or [¹²⁵]exendin(9-39) and unlabeled peptides for 120 minutes at 23° C.in 96 well plates (Nagle Nunc, Rochester, N.Y.). Incubations wereterminated by rapid filtration with cold phosphatebuffered saline, pH7.4, through polyethyleneimine-treated GF/B glass fiber filters (WallacInc., Gaithersburg, Md.) using a Tomtec Mach II plate harvester (WallacInc., Gaithersburg, Md.). Filters were dried, combined with scintillant,and radioactivity determined in a Betaplate liquid scintillant counter(Wallac Inc.).

Peptide samples were run in the assay as duplicate points at 6 dilutionsover a concentration range of 10⁻⁶M to 10⁻¹²M to generate responsecurves. The biological activity of a sample is expressed as an IC₅₀value, calculated from the raw data using an iterative curve-fittingprogram using a 4-parameter logistic equation (PRIZM®, GraphPADSoftware, La Jolla, Calif.). The results are shown in Table I.

TABLE I Compound IC₅₀ (nM) Exendin-4 [SEQ. ID. NO. 2] 0.70 Compound 1[SEQ. ID. NO. 5] 0.67 Compound 2 [SEQ. ID. NO. 6] 1.21 Compound 3 [SEQ.ID. NO. 7] 0.67 Compound 4 [SEQ. ID. NO. 8] 0.42 Compound 5 [SEQ. ID.NO. 9] 1.91 Compound 6 [SEQ. ID. NO. 10] 59.05 Compound 7 [SEQ. ID. NO.11] 5.44 Compound 8 [SEQ. ID. NO. 12] 1.75 Compound 9 [SEQ. ID. NO. 13]0.88 Compound 10 [SEQ. ID. NO. 14] 1.96 Compound 11 [SEQ. ID. NO. 15]0.69 Compound 12 [SEQ. ID. NO. 16] 2.94 Compound 13 [SEQ. ID. NO. 17]7.82 Compound 14 [SEQ. ID. NO. 18] 0.04 Compound 15 [SEQ. ID. NO. 19]0.48 Compound 16 [SEQ. ID. NO. 20] 1.10 Compound 17 [SEQ. ID. NO. 21]21.6 Compound 18 [SEQ. ID. NO. 22] 0.63 Compound 19 [SEQ. ID. NO. 23]0.63 Compound 20 [SEQ. ID. NO. 24] 0.94 Compound 21 [SEQ. ID. NO. 25]9.91 Compound 22 [SEQ. ID. NO. 26] 8.24 Compound 23 [SEQ. ID. NO. 27]0.82

Example B Cyclase Activation Study

Assay buffer contained 10 μM GTP, 0.75 mM ATP, 2.5 mM MgCl₂, 0.5 mMphosphocreatine, 12.5 U/ml creatine kinase, 0.4 mg/ml aprotinin, 1 μMIBMX in 50 mM HEPES, pH 7.4. Membranes and peptides were combined in 100ml of assay buffer in 96 well filter-bottom plates (Millipore Corp.,Bedford, Mass.). After 20 minutes incubation at 37° C., the assay wasterminated by transfer of supernatant by filtration into a fresh 96 wellplate using a Millipore vacuum manifold. Supernatant cAMP contents werequantitated by SPA immunoassay.

Peptide samples were run in the assay as triplicate points at 7dilutions over a concentration range of 10⁻⁶M to 10⁻¹²M to generateresponse curves. The biological activity of a particular sample wasexpressed as an EC₅₀ value, calculated as described above. Results aretabulated in Table II.

TABLE II Compound EC₅₀ (nM) Exendin-4 [SEQ. ID. NO. 2] 0.23 Compound 1[SEQ. ID. NO. 5] 0.3 Compound 2 [SEQ. ID. NO. 6] 0.79 Compound 3 [SEQ.ID. NO. 7] 2.35 Compound 4 [SEQ. ID. NO. 8] 0.22 Compound 5 [SEQ. ID.NO. 9] 9.85 Compound 6 [SEQ. ID. NO. 10] 79.4 Compound 7 [SEQ. ID. NO.11] 63.6 Compound 8 [SEQ. ID. NO. 12] 6.8 Compound 9 [SEQ. ID. NO. 13]1.68 Compound 10 [SEQ. ID. NO. 14] 5.37 Compound 11 [SEQ. ID. NO. 15]0.48 Compound 12 [SEQ. ID. NO. 16] 15.55 Compound 13 [SEQ. ID. NO. 17]79.6 Compound 14 [SEQ. ID. NO. 18] 1.11 Compound 15 [SEQ. ID. NO. 19]1.05 Compound 16 [SEQ. ID. NO. 20] 5.12 Compound 17 [SEQ. ID. NO. 21]43.6 Compound 18 [SEQ. ID. NO. 22] 0.76 Compound 19 [SEQ. ID. NO. 23]3.68 Compound 20 [SEQ. ID. NO. 24] 5.25 Compound 21 [SEQ. ID. NO. 25]45.1 Compound 22 [SEQ. ID. NO. 26] 20.43 Compound 23 [SEQ. ID. NO. 27]3.05

Example C Determination of Blood Glucose Levels in db/db Mice

C57BLKS/J-m-db mice at least 3 months of age were utilized for thestudy. The mice were obtained from The Jackson Laboratory and allowed toacclimate for at least one week before use. Mice were housed in groupsof ten at 22°±1° C. with a 12:12 light:dark cycle, with lights on at 6a.m.

All animals were deprived of food for 2 hours before taking baselineblood samples. Approximately 70 μl of blood was drawn from each mousevia eye puncture, after a light anesthesia with metophane. Aftercollecting baseline blood samples, to measure plasma glucoseconcentrations, all animals receive subcutaneous injections of eithervehicle (10.9% NaCl), exendin-4 or test compound (1 μg) vehicle. Bloodsamples were drawn again, using the same procedure, after exactly onehour from the injections, and plasma glucose concentrations weremeasured.

For each animal, the % change in plasma value, from baseline value, wascalculated. The percent decrease in plasma glucose after one hour isshown in Table III.

TABLE III Test Compound % drop in glucose Exendin-4 [SEQ. ID. NO. 2] 39% (n = 78) Compound 2 [SEQ. ID. NO. 6] 38% (n = 4) Compound 3 [SEQ. ID.NO. 7] 49% (n = 4) Compound 4 [SEQ. ID. NO. 8] 27% (n = 4) Compound 5[SEQ. ID. NO. 9] 47% (n = 4) Compound 6 [SEQ. ID. NO. 10] 40% (n = 5)Compound 7 [SEQ. ID. NO. 11] 31% (n = 4) Compound 8 [SEQ. ID. NO. 12]44% (n = 4) Compound 9 [SEQ. ID. NO. 13] 41% (n = 4) Compound 10 [SEQ.ID. NO. 14] 46% (n = 4) Compound 11 [SEQ. ID. NO. 15] 40% (n = 4)Compound 12 [SEQ. ID. NO. 16] 53% (n = 4) Compound 13 [SEQ. ID. NO. 17]45% (n = 4) Compound 14 [SEQ. ID. NO. 18] 54% (n = 4) Compound 15 [SEQ.ID. NO. 19] 45% (n = 4) Compound 16 [SEQ. ID. NO. 20] 54% (n = 4)Compound 17 [SEQ. ID. NO. 21] 45% (n = 4) Compound 18 [SEQ. ID. NO. 22]50% (n = 4) Compound 19 [SEQ. ID. NO. 23] 48% (n = 4) Compound 20 [SEQ.ID. NO. 24] 37% (n = 4) Compound 21 [SEQ. ID. NO. 25] 30% (n = 4)Compound 22 [SEQ. ID. NO. 26] 46% (n = 4) Compound 23 [SEQ. ID. NO. 27]42% (n = 4)

Example D Dose Response Determination of Blood Glucose Levels in db/dbMice

C57BLKS/J-m-db/db mice, at least 3 months of age were utilized for thestudy. The mice were obtained from The Jackson Laboratory and allowed toacclimate for at least one week before use. Mice were housed in groupsof ten at 22° C. 1° C. with a 12:12 light:dark cycle, with lights on at6 a.m.

All animals were deprived of food for 2 hours before taking baselineblood samples. Approximately 70 μl of blood was drawn from each mousevia eye puncture, after a light anesthesia with metophane. Aftercollecting baseline blood samples, to measure plasma glucoseconcentrations, all animals receive subcutaneous injections of eithervehicle, exendin-4 or test compound in concentrations indicated. Bloodsamples were drawn again, using the same procedure, after exactly onehour from the injections, and plasma glucose concentrations weremeasured.

For each animal, the % change in plasma value, from baseline value, wascalculated and a dose dependent relationship was evaluated usingGraphpad Prizm™ software.

FIG. 5 depicts the effects of varying doses of exendin-4 [SEQ. ID. NO.2] and Compound 3 [SEQ. ID. NO. 7] on plasma glucose levels. Exendin-4had an ED₅₀ of 0.01 μg per mouse and Compound 3 had an ED₅₀ of 0.04 μgper mouse.

Example E Gastric Emptying

The following study was carried out to examine the effects of exendin-4and exendin agonist compounds of the present invention on gastricemptying in rats. This experiment followed a modification of the methodof Scarpignato, et al., Arch. Int. Pharmacodyn. Ther. 246:286-94, 1980.

Male Harlan Sprague Dawley (HSD) rats were used. All animals were housedat 22.7±0.8 C in a 12:12 hour light:dark cycle (experiments beingperformed during the light cycle) and were fed and watered ad libitum(Diet LM-485, Teklad, Madison, Wis.). Exendin-4 was synthesizedaccording to standard peptide synthesis methods. The preparation ofCompounds 2, 3, 10 and 13 [SEQ. ID. NOS. 6, 7, 14 and 17] is describedin Examples 2, 3, 10 and 13, respectively.

The determination of gastric emptying by the method described below wasperformed after a fast of ˜20 hours to ensure that the stomach containedno chyme that would interfere with spectrophotometric absorbancemeasurements.

Conscious rats received by gavage, 1.5 ml of an acaloric gel containing1.5% methyl cellulose (M-0262, Sigma Chemical Co, St Louis, Mo.) and0.05% phenol red indicator. Twenty minutes after gavage, rats wereanesthetized using 5% halothane, the stomach exposed and clamped at thepyloric and lower esophageal sphincters using artery forceps, removedand opened into an alkaline solution which was made up to a fixedvolume. Stomach content was derived from the intensity of the phenol redin the alkaline solution, measured by absorbance at a wavelength of 560nm. In separate experiments on 7 rats, the stomach and small intestinewere both excised and opened into an alkaline solution. The quantity ofphenol red that could be recovered from the upper gastrointestinal tractwithin 20 minutes of gavage was 89±4%; dye which appeared to bindirrecoverably to the gut luminal surface may have accounted for thebalance. To account for a maximal dye recovery of less than 100%,percent of stomach contents remaining after 20 min were expressed as afraction of the gastric contents recovered from control rats sacrificedimmediately after gavage in the same experiment. Percent gastriccontents remaining=(absorbance at 20 min)/(absorbance at 0 mm)×100.

In baseline studies, with no drug treatment, gastric emptying over 20min was determined. In dose-response studies, rats were treated with0.01, 0.1, 0.3, 1, 10 and 100 μg of exendin-4, and 0.1, 0.3, 1, 10 and100 μg of Compounds 2, 3, 10 and 13 [SEQ. ID. NOS. 6, 7, 14 and 17].

The results, shown in FIGS. 6-9, show that the exendin agonists,Compounds 2, 3, 10 and 13, are potent inhibitors of gastric emptying.The EC₅₀ for exendin-4 was 0.27 μg. The EC₅₀ for Compound 2 was 0.79 μg,for Compound 3 was 0.34 μg, for Compound 10 was 0.27 μg, and forCompound 13 was 60 μg.

1. A compound consists of Xaa₁ Xaa₂ Xaa₃ Gly Xaa₅ Xaa₆ Xaa₇ Xaa₈ Xaa₉Xaa₁₀ Xaa₁₁ Xaa₁₂ Xaa₁₃ Xaa₁₄ Xaa₁₅ Xaa₁₆ Xaa₁₇ Ala Xaa₁₉ Xaa₂₀ Xaa₂₁Xaa₂₂ Xaa₂₃ Xaa₂₄ Xaa₂₅ Xaa₂₆ Xaa₂₇ Xaa₂₈-Z₁; wherein Xaa₁ is His, Argor Tyr; Xaa₂ is Ser, Gly, Ala or Thr; Xaa₃ is Asp or Glu; Xaa₅ is Ala orThr; Xaa₆ is Ala, Phe, Tyr or naphthylalanine; Xaa₇ is Thr or Ser; Xaa₈is Ala, Ser or Thr; Xaa₉ is Asp or Glu; Xaa₁₀ is Ala, Leu, Ile, Val,pentylglycine or Met; Xaa₁₁ is Ala or Ser; Xaa₁₂ is Ala or Lys; Xaa₁₃ isAla or Gln; Xaa₁₄ is Ala, Leu, Ile, pentylglycine, Val or Met; Xaa₁₅ isAla or Glu; Xaa₁₆ is Ala or Glu; Xaa₁₇ is Ala or Glu; Xaa₁₉ is Ala orVal; Xaa₂₀ is Ala or Arg; Xaa₂₁ is Ala or Leu; Xaa₂₂ is Phe, Tyr ornaphthylalanine; Xaa₂₃ is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met; Xaa₂₄ is Ala, Glu or Asp; Xaa₂₅ is Ala, Trp, Phe,Tyr or naphthylalanine; Xaa₂₆ is Ala or Leu; Xaa₂₇ is Ala or Lys; Xaa₂₈is Ala or Asn; Z₁ is —OH,

—NH₂, Gly -Z₂, Gly Gly -Z₂ Gly Gly Xaa₃₁-Z₂, Gly Gly Xaa₃₁ Ser-Z₂, GlyGly Xaa₃₁ Ser Ser-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly-Z₂, Gly Gly Xaa₃₁ SerSer Gly Ala-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆-Z₂, Gly Gly Xaa₃₁Ser Ser Gly Ala Xaa₃₆ Xaa₃₇-Z₂ or Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆Xaa₃₇ Xaa₃₈- Z₂; wherein Xaa₃₁, Xaa₃₆, Xaa₃₇ and Xaa₃₈ are independentlyselected from the group consisting of Pro, homoproline, 3Hyp, 4Hyp,thioproline, N-alkylglycine, N-alkylpentylglycine and N-alkylalanine;and Z₂ is —OH or —NH₂;

provided that no more than three of X_(aa3), X_(aa5), X_(aa6), X_(aa8),X_(aa10), X_(aa11), X_(aa12), X_(aa13), X_(aa14), X_(aa15), X_(aa16),X_(aa17), X_(aa19), X_(aa20), X_(aa21), X_(aa24), X_(aa25), X_(aa26),X_(aa27), and X_(aa28) are Ala; and a pharmaceutically acceptable saltthereof.
 2. The compound according to claim 1 wherein X_(aa1) is His orTyr.
 3. The compound according to claim 2 wherein X_(aa1) is His.
 4. Thecompound according to claim 2 wherein X_(aa2) is Gly.
 5. The compoundaccording to claim 4 wherein X_(aa14) is Leu, pentylglycine or Met. 6.The compound according to claim 5 wherein X_(aa25) is Trp or Phe.
 7. Thecompound according to claim 6 wherein X_(aa6) is Phe or naphthylalanine;and X_(aa22) is Phe or naphthylalanine; X_(aa23) is Ile or Val.
 8. Thecompound according to claim 7 wherein Z₁ is —NH₂.
 9. The compoundaccording to claim 7 wherein X_(aa31), X_(aa36), X_(aa37) and X_(aa38)are independently selected from the group consisting of Pro,homoproline, thioproline and N-alkylalanine.
 10. The compound accordingto claim 9 wherein Z₂ is —NH₂.
 11. The compound according to claim 1wherein X_(aa2) is Gly.
 12. The compound according to claim 1 whereinX_(aa14) is Leu, pentylglycine or Met.
 13. The compound according toclaim 1 wherein X_(aa25) is Trp or Phe.
 14. The compound according toclaim 1 wherein X_(aa6) is Phe or naphthylalanine; X_(aa22) is Phe ornaphthylalanine; Xaa23 is Ile or Val.
 15. The compound according toclaim 1 wherein Z₁ is —NH₂.
 16. The compound according to claim 1wherein X_(aa31), X_(aa36), X_(aa37) and X_(aa38) are independentlyselected from the group consisting of Pro, homoproline, thioproline andN-alkylalanine.
 17. The compound according to claim 1 wherein Z₂ is—NH₂.
 18. The compound according to claim 1 which has an amino acidsequence selected from SEQ ID NOs: 5 to
 65. 19. A method for thetreatment of diabetes mellitus comprising the administration of atherapeutically effective amount of a compound according to claim 18.20. The method of claim 19 further comprising the administration of atherapeutically effective amount of an insulin.
 21. The method for thetreatment of a hyperglycemic condition in a mammal comprising the stepof administering a therapeutically effective amount of a compoundaccording to claim
 18. 22. A composition comprising the compound ofclaim 1 and a pharmaceutically acceptable carrier.
 23. A method for thetreatment of diabetes mellitus comprising the administration of atherapeutically effective amount of a compound according to claim
 1. 24.The method of claim 23 further comprising the administration of atherapeutically effective amount of an insulin.
 25. The method for thetreatment of a hyperglycemic condition in a mammal comprising the stepof administering a therapeutically effective amount of a compoundaccording to claim
 1. 26. A compound consists of Xaa₁ Xaa₂ Xaa₃ Gly Xaa₅Xaa₆ Xaa₇ Xaa₈ Xaa₉ Xaa₁₀ Xaa₁₁ Xaa₁₂ Xaa₁₃ Xaa₁₄ Xaa₁₅ Xaa₁₆ Xaa₁₇ AlaXaa₁₉ Xaa₂₀ Xaa₂₁ Xaa₂₂ Xaa₂₃ Xaa₂₄ Xaa₂₅ Xaa₂₆ Xaa₂₇ Xaa₂₈-Z₁; WhereinXaa₁ is His or Arg; Xaa₂ is Gly or Ala; Xaa₃ is Asp or Glu; Xaa₅ is Alaor Thr; Xaa₆ is Ala, Phe, Tyr or naphthylalanine; Xaa₇ is Thr or Ser;Xaa₈ is Ala, Ser or Thr; Xaa₉ is Asp or Glu; Xaa₁₀ is Ala, Leu orpentylglycine; Xaa₁₁ is Ala or Ser; Xaa₁₂ is Ala or Lys; Xaa₁₃ is Ala orGln; Xaa₁₄ is Ala, Leu, or pentylglycine; Xaa₁₅ is Ala or Glu; Xaa₁₆ isAla or Glu; Xaa₁₇ is Ala or Glu; Xaa₁₉ is Ala or Val; Xaa₂₀ is Ala orArg; Xaa₂₁ is Ala or Leu; Xaa₂₂ is Phe or naphthylalanine; Xaa₂₃ is Ile,Val or tert-butyl glycine; Xaa₂₄ is Ala, Glu or Asp; Xaa₂₅ is Ala, Trpor Phe; Xaa₂₆ is Ala or Leu; Xaa₂₇ is Ala or Lys; Xaa₂₈ is Ala or Asn;Z₁ is —OH,       —NH₂,

Gly-Z₂, Gly Gly -Z₂, Gly Gly Xaa₃₁-Z₂, Gly Gly Xaa₃₁ Ser-Z₂, Gly GlyXaa₃₁ Ser Ser-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly-Z₂, Gly Gly Xaa₃₁ Ser SerGly Ala-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆-Z₂, Gly Gly Xaa₃₁ SerSer Gly Ala Xaa₃₆ Xaa₃₇-Z₂ or Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇Xaa₃₈- Z₂; wherein Xaa₃₁, Xaa₃₆, Xaa₃₇ and Xaa₃₈ are independentlyselected from the group consisting of Pro, homo- proline, thioprolineand N-alkylglycine; and Z₂ is —OH or —NH₂;

provided that no more than three of X_(aa3), X_(aa5), X_(aa6), X_(aa8),X_(aa10), X_(aa11), X_(aa12), X_(aa13), X_(aa14), X_(aa15), X_(aa16),X_(aa17), X_(aa19), X_(aa20), X_(aa21), X_(aa24), X_(aa25), X_(aa26),X_(aa27), and X_(aa28) are Ala; and a pharmaceutically acceptable saltthereof.
 27. The compound according to claim 26 which has an amino acidsequences selected from SEQ ID NOs:7-19.
 28. A method for the treatmentof diabetes mellitus comprising the administration of a therapeuticallyeffective amount of a compound according to claim
 27. 29. The method ofclaim 28 further comprising the administration of a therapeuticallyeffective amount of an insulin.
 30. A composition comprising thecompound of claim 26 and a pharmaceutically acceptable carrier.
 31. Amethod for the treatment of diabetes mellitus comprising theadministration of a therapeutically effective amount of a compoundaccording to claim
 26. 32. The method of claim 31 further comprising theadministration of a therapeutically effective amount of an insulin. 33.A compound consists of Xaa₁ Xaa₂ Xaa₃ Gly Xaa₅ Xaa₆ Xaa₇ Xaa₈ Xaa₉ Xaa₁₀Xaa₁₁ Xaa₁₂ Xaa₁₃ Xaa₁₄ Xaa₁₅ Xaa₁₆ Xaa₁₇ Ala Xaa₁₉ Xaa₂₀ Xaa₂₁ Xaa₂₂Xaa₂₃ Xaa₂₄ Xaa₂₅ Xaa₂₆ X₁-Z₁; Wherein Xaa₁ is His, Arg, Tyr or4-imidazopropionyl; Xaa₂ is Ser, Gly, Ala or Thr; Xaa₃ is Asp or Glu;Xaa₅ is Ala or Thr; Xaa₆ is Ala, Phe, Tyr or naphthylalanine; Xaa₇ isThr or Ser; Xaa₈ is Ala, Ser or Thr; Xaa₉ is Asp or Glu; Xaa₁₀ is Ala,Leu, Ile, Val, pentylglycine or Met; Xaa₁₁ is Ala or Ser; Xaa₁₂ is Alaor Lys; Xaa₁₃ is Ala or Gln; Xaa₁₄ is Ala, Leu, Ile, pentylglycine, Valor Met; Xaa₁₅ is Ala or Glu; Xaa₁₆ is Ala or Glu; Xaa₁₇ is Ala or Glu;Xaa₁₉ is Ala or Val; Xaa₂₀ is Ala or Arg; Xaa₂₁ is Ala, Leu orLys-NH^(ε)-R Asn, Asn Lys- NH^(ε)-R; Lys-NH^(ε)-R Ala; Ala Lys-NH^(ε)-Rwherein R is Lys, Arg, C₁-C₁₀ straight chain or branched alkanoyl orcycloalkylalkanoyl; Xaa₂₂ is Phe, Tyr or naphthylalanine; Xaa₂₃ is Ile,Val, Leu, pentylglycine or tert- butyl glycine; Xaa₂₄ is Ala, Glu orAsp; Xaa₂₅ is Ala, Trp, Phe, Tyr or naphthylalanine; Xaa₂₆ is Ala orLeu; X₁ is Lys Asn, Asn Lys, Lys-NH^(ε)-R Asn, Asn Lys- NH^(ε)-R,Lys-NH^(ε)-R Ala, Ala Lys-NH^(ε)-R wherein R is Lys, Arg, C₁-C₁₀straight chain or branched alkanoyl or cycloalkylalkanoyl; and Z₁ is—OH,       —NH₂,

Gly-Z₂, Gly Gly-Z₂ Gly Gly Xaa₃₁-Z₂, Gly Gly Xaa₃₁ Ser-Z₂, Gly Gly Xaa₃₁Ser Ser-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly-Z₂, Gly Gly Xaa₃₁ Ser Ser GlyAla-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆-Z₂, Gly Gly Xaa₃₁ Ser SerGly Ala Xaa₃₆ Xaa₃₇-Z₂ or Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇Xaa₃₈- Z₂; wherein Xaa₃₁, Xaa₃₆, Xaa₃₇ and Xaa₃₈ are independentlyselected from the group consisting of Pro, homoproline, 3Hyp, 4Hyp,thioproline, N-alkylglycine, N-alkylpentylglycine and N-alkylalanine;and Z₂ is —OH or —NH₂;

provided that no more than three of X_(aa3), X_(aa5), X_(aa6), X_(aa8),X_(aa10), X_(aa11), X_(aa12), X_(aa13), X_(aa14), X_(aa15), X_(aa16),X_(aa17), X_(aa19), X_(aa20), X_(aa21), X_(aa24), X_(aa25), X_(aa26),X_(aa27), and X_(aa28) are Ala; and a pharmaceutically acceptable saltthereof.
 34. The compound according to claim 33 wherein X_(aa1) is His,Tyr, or 4-imidazopropionyl.
 35. The compound according to claim 34wherein X_(aa1) is His.
 36. The compound according to claim 34 whereinX_(aa1) is 4-imidazopropionyl.
 37. The compound according to claim 33wherein X_(aa2) is Gly.
 38. The compound according to claim 33 whereinX_(aa14) is Leu, pentylglycine, or Met.
 39. The compound according toclaim 33 wherein X_(aa25) is Trp or Phe.
 40. The compound according toclaim 33 wherein X_(aa6) is Phe or naphthylalanine; X_(aa22) is Phe ornaphthylalanine; and X_(aa23) is Ile or Val.
 41. The compound accordingto claim 33 wherein Z₁ is —NH₂.
 42. The compound according to claim 33wherein X_(aa31), X_(aa36), X_(aa37) and X_(aa38) are independentlyselected from the group consisting of Pro, homoproline, thioproline, andN-alkylalanine.
 43. The compound according to claim 33 wherein Z₂—NH₂.44. The A compound according to claim 33 wherein X₁ is Lys Asn,Lys-NH^(ε)—R Asn, or Lys-NH^(ε)—R Ala wherein R is Lys, Arg, C₁-C₁₀straight chain or branched alkanoyl.
 45. The compound according to claim33 wherein X_(aa21) is Lys-NH^(ε)—R where R is Lys, Arg, C₁-C₁₀ straightchain or branched alkanoyl or cycloalkylkanoyl.
 46. A compositioncomprising the compound of claim 33 and a pharmaceutically acceptablecarrier.
 47. A compound comprising the acid sequence of SEQ ID NO:6, 67,68, 69, 70, 71, 72, 73, or
 74. 48. A composition comprising the compoundof claim 47 and a pharmaceutically acceptable carrier.